Benzazepine derivatives useful as vasopressin antagonists

ABSTRACT

The present invention provides a benzazepine compound that can maintain for a long period of time the blood level of tolvaptan enabling to provide the desired pharmaceutical effects. The benzazepine compound of the present invention is represented by general formula (1) 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a —CO—(CH 2 ) n —COR 2  group (wherein n is an integer of 1 to 4, and R 2  is (2-1) a hydroxy group; (2-2) a lower alkoxy group optionally substituted with a hydroxy group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyloxy group, a cycloalkyloxycarbonyloxy group, or 5-methyl-2-oxo-1,3-dioxo-4-yl; or (2-3) an amino group optionally substituted with a hydroxy-lower alkyl group), or the like.

TECHNICAL FIELD

The present invention relates to a novel benzazepine compound and apharmaceutical preparation.

BACKGROUND ART

Tolvaptan represented by the following formula (2) is a known compound,and is disclosed, for example, in U.S. Pat. No. 5,258,510 (Example1199).

Tolvaptan is known to be useful as a vasopressin antagonist havingaquaretic efficacy (Circulation, 107, pp. 2690-2696 (2003)). However,because of its low water solubility, tolvaptan has problems in that itis poorly absorbed from the gastrointestinal tract, and its dosage formand administration route are limited. From the viewpoint of medicaltreatment, the development of a new drug that can maintain for a longperiod of time the blood level of tolvaptan enabling to provide thedesired pharmaceutical effects has been desired.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel benzazepinecompound that has excellent properties, such as the maintenance of theblood level of tolvaptan for a long period of time enabling to providethe desired pharmaceutical effects.

The present inventors carried out extensive research to overcome theabove problem, and as a result found that benzazepine compoundsrepresented by general formula (1) have excellent properties, such asthe maintenance of pharmaceutical effects of the active ingredienttolvaptan for a long period of time in the body. The present inventionhas been accomplished based on the above findings.

The present invention provides the following benzazepine compounds, andpharmaceutical preparations containing the compounds shown in Items 1 to3 below.

Item 1. A benzazepine compound represented by general formula (1)

wherein R¹ is a group of (1-1) to (1-7):

(1-1) a —CO—(CH₂)_(n)—COR² group wherein n is an integer of 1 to 4, R²is (2-1) a hydroxy group; (2-2) a lower alkoxy group optionallysubstituted with a hydroxy group, a lower alkanoyl group, a loweralkanoyloxy group, a lower alkoxycarbonyloxy group, acycloalkyloxycarbonyloxy group, or 5-methyl-2-oxo-1,3-dioxol-4-yl; or(2-3) an amino group optionally substituted with a hydroxy-lower alkylgroup;

(1-2) a —CO—(CH₂)_(m)—NR³R⁴ group wherein m is an integer of 0 to 4, R³is a hydrogen atom or a lower alkyl group, R⁴ is (4-1) a hydrogen atom;(4-2) a lower alkyl group optionally substituted with a halogen atom, alower alkylamino group, a lower alkoxycarbonyl group, or5-methyl-2-oxo-1,3-dioxol-4-yl; or (4-3) a lower alkoxycarbonyl groupoptionally substituted with a halogen atom, a lower alkanoyloxy group,or 5-methyl-2-oxo-1,3-dioxol-4-yl, R³ and R⁴ may form a 5- to 6-memberedsaturated heterocyclic ring by bonding R³ and R⁴ to each other, togetherwith the nitrogen atom to which R³ and R⁴ bond, directly or via anitrogen atom or oxygen atom, the heterocyclic ring being optionallysubstituted with (4-4) a lower alkyl group optionally substituted with ahydroxy-lower alkoxy group; (4-5) a lower alkoxycarbonyl group; (4-6) analkylcarbonyl group (optionally substituted on the alkyl group with acarboxyl group or a lower alkoxycarbonyl group); (4-7) an arylcarbonylgroup; or (4-8) a furylcarbonyl group;

(1-3) a —CO—(CH₂)_(p)—O—CO—NR⁵R⁶ group wherein p is an integer of 1 to4, R⁵ is a lower alkyl group, and R⁶ is a lower alkoxycarbonyl-loweralkyl group;

(1-4) a —CO—(CH₂)_(q)—X—R⁷ group wherein q is an integer of 1 to 4, X isan oxygen atom, a sulfur atom, or a sulfonyl group, and R⁷ is acarboxy-lower alkyl group, or a lower alkoxycarbonyl lower alkyl group;

(1-5) a —CO—R⁸ group (wherein R⁸ is (8-1) an alkyl group optionallysubstituted with a halogen atom, a lower alkanoyloxy group, or a phenylgroup (substituted with a dihydroxy phosphoryloxy group in which thehydroxy groups are optionally substituted with benzyl groups, and alower alkyl group), (8-2) a lower alkoxy group substituted with ahalogen atom, a lower alkanoyloxy group, or a dihydroxyphosphoryloxygroup, (8-3) a pyridyl group, or (8-4) a lower alkoxyphenyl group;

(1-6) a lower alkyl group substituted with a group selected from thegroup consisting of lower alkylthio groups, a dihydroxyphosphoryloxygroup, and lower alkanoyloxy groups; and

(1-7) an amino acid or peptide residue optionally protected with one ormore protecting groups; or a salt thereof.

Item 2. The compound according to Item 1, wherein, in formula (1), R¹ isa group selected from the group consisting of: —CO—(CH₂)_(n)—COOH,wherein n is an integer of 1 to 4; —CO—R⁸, wherein R⁸ is an alkyl group;and, an amino acid or peptide residue optionally protected with one ormore protecting groups; or a salt thereof.Item 3. The compound according to Item 1, wherein, in formula (1), R¹ isalanyl, sarcosyl, N-ethylglycyl, N-propylglycyl, N-methyl-N-ethylglycyl,N-methyl-N-propylglycyl, N-methyl-N-butylglycyl,N-methyl-N-pentylglycyl, or N-methyl-N-hexylglycyl; or a peptide residueselected from the group consisting of: sarcosyl-glycyl, glycyl-glycyl,glycyl-sarcosyl, glycyl-alanyl, alanyl-glycyl, sarcosyl-sarcocyl,glycyl-phenylalanyl, phenylalanyl-glycyl, phenylalanyl-phenylalanyl,glycyl-glycyl-glycyl, N,N-dimethylglycyl-glycyl,N-methyl-N-ethylglycyl-glycyl, sarcosyl-glycyl-glycyl, andN,N-dimethylglycyl-glycyl-glycyl, each of which is optionally protectedwith one or more protecting groups; or a salt thereof.Item 4. The compound according to Item 3, wherein, in formula (1), R¹ isa peptide residues selected from the group consisting of:sarcosyl-glycyl, glycyl-glycyl, glycyl-sarcosyl, glycyl-alanyl,alanyl-glycyl, glycyl-phenylalanyl, phenylalanyl-glycyl,phenylalanyl-phenylalanyl, glycyl-glycyl-glycyl,N,N-dimethylglycyl-glycyl, N-methyl-N-ethylglycyl-glycyl, andN,N-dimethylglycyl-glycyl-glycyl, each of which is optionally protectedwith one or more protecting groups; or a salt thereof. Item 5. Apharmaceutical preparation comprising the benzazepine compound of Item 1or a pharmacologically acceptable salt thereof, and a pharmacologicallyacceptable diluent and/or carrier.Item 6. The pharmaceutical preparation according to Item 5 which is usedas a vasodilator, hypotensive drug, aquaretic agent, or plateletaggregation inhibitor.

Specific examples of the groups in general formula (1) are as follows.

In this specification, the term “lower” refers to “C₁₋₆”, unlessotherwise specified.

Examples of lower alkanoyl groups include straight or branched C₂₋₆alkanoyl groups, such as acetyl, n-propionyl, n-butyryl, isobutyryl,n-pentanoyl, tert-butyl carbonyl, and n-hexanoyl.

Examples of lower alkanoyloxy groups include straight or branched C₂₋₆alkanoyloxy groups, such as acetyloxy, n-propionyloxy, n-butyryloxy,isobutyryloxy, n-pentanoyloxy, tert-butylcarbonyloxy, and n-hexanoyloxygroup.

Examples of lower alkoxycarbonyloxy groups include alkoxycarbonyloxygroups in which the alkoxy moiety is a straight or branched C₁₋₆ alkoxygroup, such as methoxycarbonyloxy, ethoxycarbonyloxy,n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-buthoxycarbonyloxy,isobuthoxycarbonyloxy, tert-buthoxycarbonyloxy, sec-buthoxycarbonyloxy,n-pentyloxycarbonyloxy, neopentyloxycarbonyloxy, n-hexyloxycarbonyloxy,isohexyloxycarbonyloxy, and 3-methyl pentyloxycarbonyloxy.

Examples of cycloalkyloxycarbonyloxy groups includecycloalkyloxycarbonyloxy groups in which the cycloalkyl moiety is a C₃₋₈cycloalkyl group, such as cyclopropyloxycarbonyloxy,cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy,cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy, andcyclooctyloxycarbonyloxy.

Examples of cycloalkylcarbonyl groups include cycloalkylcarbonyl groupsin which the cycloalkyl moiety is a C₃₋₈ cycloalkyl group, such ascyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cycloheptylcarbonyl, and cyclooctylcarbonyl.

Examples of lower alkoxy groups include straight or branched C₁₋₆ alkoxygroups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy,neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of hydroxy-lower alkyl groups include straight or branched C₁₋₆alkyl groups having one to three hydroxy groups, such as hydroxymethyl,2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl,4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,5-hydroxypentyl, 6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl,2-methyl-3-hydroxypropyl, and 2,3,4-trihydroxybutyl.

Examples of lower alkyl groups include straight or branched C₁₋₆ alkylgroups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,isohexyl, and 3-methylpentyl.

Examples of halogen atoms include fluorine, chlorine, bromine, andiodine.

Examples of lower alkylamino groups include amino groups substitutedwith one to two straight or branched C₁₋₆ alkyl groups, such asmethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino,diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino,di-n-hexylamino, N-methyl-N-ethylamino, N-ethyl-N-n-propylamino,N-methyl-N-n-butylamino, and N-methyl-N-n-hexylamino.

Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groups inwhich the alkoxy moiety is a straight or branched C₁₋₆ alkoxy group,such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl,neopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, and3-methylpentyloxycarbonyl.

Examples of 6-membered saturated heterocyclic rings formed by bonding R³and R⁴ to each other, together with the nitrogen atom to which R³ and R⁴bond, directly or via a nitrogen atom or oxygen atom include piperazine,piperidine, morpholine, and the like.

Examples of hydroxy-lower alkoxy groups include hydroxyalkoxy groupsthat have one or two hydroxy groups, the alkoxy moiety being a straightor branched C₁₋₆ alkoxy group, such as hydroxymethoxy, 2-hydroxyethoxy,1-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 5-hydroxypentyloxy,6-hydroxyhexyloxy, 1,1-dimethyl-2-hydroxyethoxy, and2-methyl-3-hydroxypropoxy.

Examples of alkylcarbonyl groups include alkylcarbonyl groups in whichthe alkyl moiety is a straight or branched C₁₋₂₀ alkyl group, such asmethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl,sec-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl,neopentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl,3-methylpentylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl,n-nonylcarbonyl, n-decylcarbonyl, n-undecylcarbonyl, n-dodecylcarbonyl,n-tridecylcarbonyl, n-tetradecylcarbonyl, n-pentadecylcarbonyl,n-hexadecylcarbonyl, n-heptadecylcarbonyl, n-octadecylcarbonyl,n-nonadecylcarbonyl, and n-icosylcarbonyl.

Examples of arylcarbonyl groups include phenylcarbonyl, (1- or2-)naphthylcarbonyl, and the like.

Examples of furylcarbonyl groups include (2- or 3-)furylcarbonyl.

Examples of lower alkoxycarbonyl lower alkyl groups includealkoxycarbonylalkyl groups in which the alkoxy moiety is a straight orbranched C₁₋₆ alkoxy group, and the alkyl moiety is a straight orbranched C₁₋₆ alkyl group, such as methoxycarbonylmethyl,ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,1-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl,4-ethoxycarbonylbutyl, 5-isopropoxycarbonyl pentyl,6-n-propoxycarbonylhexyl, 1,1-dimethyl-2-n-butoxycarbonylethyl,2-methyl-3-tert-butoxycarbonylpropyl, 2-n-pentyloxycarbonylethyl, andn-hexyloxycarbonylmethyl.

Examples of carboxy lower alkyl groups include carboxy alkyl groups inwhich the alkyl moiety is a straight or branched C₁₋₆ alkyl group, suchas carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl,4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl,1,1-dimethyl-2-carboxyethyl, and 2-methyl-3-carboxypropyl.

Examples of lower alkoxy phenyl groups include alkoxyphenyl groups inwhich the alkoxy moiety is a straight or branched C₁₋₆ alkoxy group,such as methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, isopropoxyphenyl,n-butoxyphenyl, isobutoxyphenyl, tert-butoxyphenyl, sec-butoxyphenyl,n-pentyloxyphenyl, isopentyloxyphenyl, neopentyloxyphenyl,n-hexyloxyphenyl, isohexyloxyphenyl, and 3-methylpentyloxyphenyl.

Examples of lower alkylthio groups include a straight or branched C₁₋₆alkylthio groups, such as methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, tert-butylthio, n-pentylthio, andn-hexylthio.

Examples of amino acid or peptide residues include amino acid residuessuch as alanyl, phenylalanyl, sarcosyl, valyl, leucyl, isoleucyl,prolyl, N-ethylglycyl, N-propylglycyl, N-isopropylglycyl, N-butylglycyl,N-tert-butylglycyl, N-pentylglycyl, N-hexylglycyl, N,N-diethylglycyl,N,N-dipropylglycyl, N,N-dibutylglycyl, N,N-dipentylglycyl,N,N-dihexylglycyl, N-methyl-N-ethylglycyl, N-methyl-N-propylglycyl,N-methyl-N-butylglycyl, N-methyl-N-pentylglycyl, andN-methyl-N-hexylglycyl; and peptide residues such as sarcosyl-glycyl,glycyl-glycyl, glycyl-sarcosyl, sarcosyl-sarcosyl, alanyl-glycyl,phenylalanyl-glycyl, phenylalanyl-phenylalanyl, glycyl-glycyl-glycyl,N-ethylglycyl-glycyl, N-propylglycyl-glycyl, N,N-dimethylglycyl-glycyl,N,N-diethylglycyl-glycyl, N-methyl-N-ethylglycyl-glycyl,sarcosyl-glycyl-glycyl, N-ethylglycyl-glycyl-glycyl, andN,N-dimethylglycyl-glycyl-glycyl.

Examples of protecting groups for amino acids and peptides include thoseusually used to protect amino groups of amino acids or peptides, such astert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, andacetyl.

The benzazepine compounds represented by general formula (1) can beprepared by various methods; for example, by the processes according tothe following Reaction Schemes.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, Compound (1a) wherein R¹ is a group of (1-1) to (1-5) or(1-7) above can be prepared from tolvaptan of formula (2) according toReaction Scheme-1, 2, or 3.

wherein R is —(CH₂)_(n)—COR² (wherein n and R² are as defined above),—(CH₂)_(m)—NR³R⁴ (wherein m, R³ and R⁴ are as defined above),—(CH₂)_(p)—O—CO—NR⁵R⁶ (wherein p, R⁵ and R⁶ are as defined above),—(CH₂)_(q)—X—R⁷ (wherein q, X, and R⁷ areas defined above), —R⁸ (whereinR⁸ is as defined above), or a group formed by removing a carbonyl group(CO group) from an amino acid or peptide residue optionally protectedwith one or more protecting groups (e.g., aminomethyl for glycyl,(R)-1-aminoethyl for alanyl, (R)-1-amino-2-phenylpropyl forphenylalanyl, (methylamino)methyl for sarcosyl,(R)-1-amino-3-methylbutyl for leucyl,tert-butoxycarbonyl(ethyl)aminomethyl forN-tert-butoxycarbonyl-N-ethylglycyl, (S)-2-amino-propanamidomethyl foralanyl-glycyl, 2-(methylamino)acetamido-methyl for sarcosyl-glycyl,(S)-2-amino-3-phenylpropanamidomethyl for phenylalanyl-glycyl,(2-aminoacetamido)acetamidomethyl for glycyl-glycyl-glycyl,[2-(methylamino)acetamido]acetamidomethyl for sarcosyl-glycyl-glycyl, orthe like.).

According to the process shown in Reaction Scheme-1, Compound (1a) isprepared by reacting Compound (2) with an acid anhydride (3) in thepresence or absence of a basic compound in a suitable solvent.

The amount of acid anhydride (3) is usually about 1 mole to a largeexcess, and preferably about 1 to about 10 moles, per mole of Compound(2).

The solvent may be any known solvent that does not adversely affect thereaction. Examples of such solvents include ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; esters such as ethyl acetate; aromatichydrocarbons such as benzene, toluene, and xylene; aprotic polarsolvents such as acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and N-methylpyrrolidone (NMP); and mixed solventsthereof.

Examples of basic compounds include triethylamine, pyridine, and thelike. The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (2). Such abasic compound can also be used as the solvent.

When a catalyst such as 4-dimethylaminopyridine is present in thereaction system in the above reaction, the reaction can be promoted.

The reaction temperature of the above reaction is usually roomtemperature to 150° C., and preferably room temperature to 100° C. Thereaction time is usually 15 minutes to 24 hours, preferably 30 minutesto 6 hours, and more preferably 1 to 3 hours.

wherein R is as defined above, and X¹ is a halogen atom.

According to the process shown in Reaction Scheme-2, Compound (2) isreacted with an acid halide (4) in the presence of a basic compound in asuitable solvent to prepare Compound (1a).

The amount of acid halide (4) is usually about 1 mole to a large excess,and preferably about 1 to about 10 moles, per mole of Compound (2).

The solvent may be any known solvent that does not adversely affect thereaction. Examples of such solvents include ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; esters such as ethyl acetate; aromatichydrocarbons such as benzene, toluene, and xylene; aprotic polarsolvents such as acetonitrile, DMF, DMSO, and NMP; and mixed solventsthereof.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, and cesium carbonate; phosphates such as potassium phosphate,and sodium phosphate; organic bases such as pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), and 1,4-diazabicyclo [2.2.2]octane (DABCO); and mixtures thereof.

The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (2). Such anorganic base can also be used as the solvent.

When a catalyst such as 4-dimethylaminopyridine is present in thereaction system in the above reaction, the reaction can be promoted.

The reaction temperature of the above reaction is usually −10° C. to100° C., and preferably 0° C. to 50° C., and more preferably 0° C. toroom temperature. The reaction time is usually 15 minutes to 24 hours,preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours.

wherein R is as defined above.

According to the process shown in Reaction Scheme-3, Compound (2) iscondensed with a carboxylic acid (5) in the presence of an activator toprepare Compound (1a).

The amount of carboxylic acid (5) is usually about 1 to about 10 moles,and preferably about 1 to about 5 moles, per mole of Compound (2).

Examples of activators include dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC),carbonyldiimidazole, and the like. Such activators can be used singly orin a combination of two or more.

The amount of activator is usually at least about 1 mole, and preferablyabout 1 mole to about 5 moles, per mole of Compound (2).

The condensation reaction is usually carried out in a suitable solventin the presence or absence of a basic compound. Examples of solventsthat can be used include ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, and diglyme; halogenated hydrocarbons suchas methylene chloride, chloroform, 1,2-dichloroethane, and carbontetrachloride; esters such as ethyl acetate; aromatic hydrocarbons suchas benzene, toluene, and xylene; aprotic polar solvents such asacetonitrile, DMF, DMSO, and NMP; and mixed solvents thereof.

Examples of basic compounds include triethylamine, pyridine, and thelike. The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (2). Such abasic compound can also be used as the solvent.

When a catalyst such as 4-dimethylaminopyridine is present in thereaction system, the reaction can be promoted.

The reaction is usually carried out at about −20° C. to about 100° C.,and preferably at 0° C. to room temperature. The reaction usuallycompletes in about 5 minutes to about 90 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, Compound (1b) wherein R¹ is a group of (1-6) above (alower alkyl group substituted with a lower alkylthio group) can beprepared from tolvaptan of formula (2) by the process according to thefollowing Reaction Scheme-4:

wherein R^(1a) is a lower alkyl group substituted with a lower alkylthiogroup.

The process shown in Reaction Scheme-4 is a reaction to convert thehydrogen atom of the hydroxy group of Compound (2) into a lower alkylgroup substituted with a lower alkylthio group. For example, to convertthe hydrogen atom of the hydroxy group of Compound (2) into amethylthiomethyl group, Compound (2) is subjected to the commonether-bond-formation reaction, so-called Pummerer reaction, or the like.The common ether-bond-formation reaction is usually carried out in aconventional solvent that does not affect the reaction, and the reactiontemperature is not critical. The Pummerer reaction is as shown inReaction Scheme-4-1 below; the compound (2) is reacted with sulfoxide(6), such as dimethyl sulfoxide, in the presence of acetic anhydride andacetic acid at room temperature to about 70° C. for about 4 to about 79hours.

wherein R^(1b) and R^(1c) are independently a lower alkyl group. Amongthe benzazepine compounds represented by general formula (1) or saltsthereof, Compound (1c) wherein R¹ is a group of (1-6) above (a loweralkyl group substituted with a dihydroxyphosphoryloxy group) can beprepared, for example, from Compound (1b) by the process according tothe following Reaction Scheme-5:

wherein R^(1b) is a lower alkyl group substituted with adihydroxyphosphoryloxy group, and R^(1a) is as defined above.

The process shown in Reaction Scheme-5 is a reaction to convert thelower alkyl group substituted with a lower alkylthio group of R¹ into alower alkyl group substituted with a dihydroxyphosphoryloxy group. Forexample, to convert the methylthiomethyl group of R¹ into adihydroxyphosphoryloxymethyl group, as shown in Reaction Scheme-5-1below, Compound (1b″) is reacted with a halogenating agent (for example,sulfuryl chloride, N-iodosuccinimide, etc.), and the obtained compoundis then reacted with phosphoric acid in the presence of a basiccompound.

wherein r is integer which may range from 1 to 4 and R^(1e) is a loweralkyl group.

The reaction of Compound (1b″) with the halogenating agent is preferablycarried out in a halogenated hydrocarbon (for example, methylenechloride, 1,2-dichloroethane, etc.) at about room temperature. Theamount of halogenating agent is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1b″). Thisreaction completes in about 5 minutes to about 1 hour.

Subsequently, the reaction of the obtained compound with phosphoric acidis preferably carried out in the presence of an inert organic solvent(for example, tetrahydrofuran, acetonitrile, etc.). The amount ofphosphoric acid is usually at least about 1 mole, and preferably about 1to about 10 moles, per mole of Compound (1b″). Examples of basiccompounds include carbonates such as sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, andcesium carbonate; phosphates such as potassium phosphate, and sodiumphosphate; organic bases such as pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine, DBN, DBU, andDABCO; and mixtures thereof. The amount of basic compound is usually atleast about 1 mole, and preferably about 1 to about 10 moles, per moleof Compound (1b″). The reaction temperature of the above reaction isusually room temperature to about 200° C., and preferably about 50° C.to about 150° C. The reaction usually completes in about 10 minutes toabout 10 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, Compound (1d) wherein R¹ is a group of (1-6) above (alower alkyl group substituted with a lower alkanonyloxy group) can beprepared, for example, from Compound (1b) by the process according tothe following Reaction Scheme-6:

wherein R^(1f) is a lower alkyl group substituted with a loweralkanoyloxy group, and R^(1a) is as defined above.

The process shown in Reaction Scheme-6 is a reaction to convert thelower alkyl group substituted with a lower alkylthio group of R¹ into alower alkyl group substituted with a lower alkanoyloxy group. Forexample, as shown in Reaction Scheme-6-1 below, Compound (1b″) isreacted with a halogenating agent (for example, sulfuryl chloride,N-iodosuccinimide, etc.), and the obtained compound is then reacted withcarboxylic acid or a salt thereof.

wherein R^(1g) is a lower alkyl group and R^(1e) are as defined above.

The reaction of Compound (1b″) with the halogenating agent is preferablycarried out in a halogenated hydrocarbon (for example, methylenechloride, 1,2-dichloroethane, etc.) at about room temperature. Theamount of halogenating agent is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1b″). Thisreaction completes in about 5 minutes to about 1 hour.

Subsequently, the reaction of the obtained compound with carboxylic acidor a salt thereof is preferably carried out in the presence of an inertorganic solvent (for example, tetrahydrofuran, acetonitrile, etc.). Theamount of carboxylic acid is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1b). Thereaction temperature is usually room temperature to about 200° C., andpreferably about 50° C. to about 150° C. The reaction time is usuallyabout 10 minutes to about 10 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, Compound (1f) wherein R¹ is a group of (1-1) above, andR² is a group of (2-2) above can be prepared from Compound (1e) whereinR¹ is a group of (1-1) above, and R² is a group of (2-1) above by theprocess according to the following Reaction Scheme-7:

wherein R^(2a) is a lower alkoxy group optionally substituted with ahydroxy, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyloxy,cycloalkyloxycarbonyloxy, or 5-methyl-2-oxo-1,3-dioxol-4-yl group,R^(2a′) is a lower alkoxy group optionally substituted with a hydroxy,lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyloxy,cycloalkyloxycarbonyloxy, or 5-methyl-2-oxo-1,3-dioxol-4-yl group, and nand X′ are as defined above.

The reaction of Compound (1e) with Compound (8) is carried out in thepresence of a basic compound in a suitable solvent.

The amount of compound (8) is usually about 1 mole to a large excess,and preferably about 1 to about 10 moles, per mole of Compound (1e).

Examples of reaction solvents include ethers such as diethyl ether,dioxane, tetrahydrofuran, monoglyme, and diglyme; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; esters such as ethyl acetate; aromatichydrocarbons such as benzene, toluene, and xylene; aprotic polarsolvents such as acetonitrile, DMF, DMSO, and NMP; and mixed solventsthereof.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, and cesium carbonate; phosphates such as potassium phosphate,and sodium phosphate; organic bases such as pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine, DBN, DBU, andDABCO; and the like. Such compounds can be used singly or in acombination of two or more. The amount of basic compound is usually atleast about 1 mole, and preferably about 1 to about 10 moles, per moleof Compound (1e). Such a basic compound can also be used as the solvent.

The reaction temperature is usually room temperature to 150° C., andpreferably room temperature to 100° C. The reaction time is usually 15minutes to 24 hours, preferably 30 minutes to 6 hours, and morepreferably 1 to 3 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, Compound (1g) wherein R¹ is a group of (1-1) above, andR² is an amino group substituted with one or more hydroxy-lower alkylgroups, can be prepared, for example, from Compound (1e) wherein R¹ is agroup of (1-1) above, and R² is a group of (2-1) above by the processaccording to the following Reaction Scheme-8:

wherein R^(2b) is an amino group substituted with one or morehydroxy-lower alkyl groups, and n is as defined above.

The reaction of Compound (1e) with Compound (9) is carried out underreaction conditions commonly used for the carbodiimide method. Morespecifically, Compound (1e) is condensed with Compound (9) in thepresence of an activator such as dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), orcarbonyldiimidazole.

The amount of activator is usually at least about 1 mole, and preferablyabout 1 to about 5 moles, per mole of Compound (1e).

The condensation reaction is carried out in a suitable solvent in thepresence or absence of a basic compound. Examples of solvents that canbe used include ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme, and diglyme; halogenated hydrocarbons such as methylenechloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride;esters such as ethyl acetate; aromatic hydrocarbons such as benzene,toluene, and xylene; aprotic polar solvents such as acetonitrile, DMF,DMSO, and NMP; and mixed solvents thereof.

Examples of basic compounds include triethylamine, pyridine, and thelike. The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1e). Such abasic compound can also be used as the solvent.

When WSC is used as an activator in the above reaction, the presence ofa catalyst, such as 1-hydroxybenzotriazole (HOBt), in the reactionsystem can promote the reaction.

The reaction is usually carried out at about −20° C. to about 180° C.,and preferably about 0° C. to about 150° C. The reaction usuallycompletes in about 5 minutes to about 90 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, compounds in which the amino group is protected by aprotecting group can be converted by deprotection into the correspondingcompounds wherein the amino group is not protected by the protectinggroup, for example, by the process shown in the following ReactionScheme-9:

wherein R^(1h) is the same as above R¹ having amino group, of which thesaid amino group is protected with an amino-protective group; R^(1i) isthe same as above R¹ having amino group corresponding to R^(1h), ofwhich the amino-protective group is deprotected.

The reaction of converting Compound (1h) into Compound (1i) is carriedout in the presence of an acid in a suitable solvent or without usingany solvent.

Examples of solvents that can be used include water; lower alcohols suchas methanol, ethanol, isopropanol, and tert-butanol; ketones such asacetone, and methyl ethyl ketone; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, and diglyme; fatty acids such as aceticacid, and formic acid; esters such as methyl acetate, and ethyl acetate;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane, and carbon tetrachloride; amides such as DMF,N,N-dimethylacetamide, and NMP; DMSO; hexamethylphosphoric triamide; andmixed solvents thereof.

Examples of acids include mineral acids such as hydrochloric acid,sulfuric acid, and hydrobromic acid; and organic acids, for example,carboxylic acids such as formic acid, acetic acid, and trifluoroaceticacid, and sulfonic acids such as p-toluenesulfonic acid.

The amount of acid is usually at least about 1 mole, and preferablyabout 1 to 10 moles, per mole of Compound (1h). A large excess of acidcan be used as the solvent.

The reaction is usually carried out at about 0° C. to about 200° C., andpreferably at 0° C. to about 150° C. The reaction usually completes inabout 10 minutes to about 30 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, compounds having a halogen atom in R¹ can be reacted withan amine to convert the halogen atom into corresponding amino group, forexample, by the process shown in the following Reaction Scheme-10:

wherein is the same as above R¹ having halogen atom, and R^(1k) is thegroup of which the halogen atom of R^(ij) is converted to the aminogroup corresponding to the reactant amine.

The reaction of Compound (1j) with amine is carried out in a suitableinert solvent in the presence of a basic compound.

Examples of inert solvents include aromatic hydrocarbons such asbenzene, toluene, and xylene; ethers such as diethyl ether,tetrahydrofuran, dioxane, monoglyme, and diglyme; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform, andcarbon tetrachloride; ketones such as acetone, and methyl ethyl ketone;acetonitrile, DMSO, DMF, hexamethylphosphoric triamide; and mixedsolvents thereof.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, and cesium carbonate; organic bases such as pyridine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, DBN,DBU, and DABCO. Such bases can be used singly or in a combination of twoor more.

The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1j).

The amount of amine (8) is usually at least about 1 mole, and preferablyabout 1 to about 10 moles, per mole of Compound (1j).

Alkali metal halides such as sodium iodide and potassium iodide, andother compounds may be present in the reaction system of this reaction.

The reaction is usually carried out at about 0° C. to about 200° C., andpreferably at 0° C. to about 150° C. The reaction usually completes inabout 5 minutes to about 80 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, compounds having an amino group in R¹ can be subjected toreductive alkylation to convert the amino group into a N-alkylaminogroup.

wherein R^(1l) is the same as above R¹ having amino group, and R^(1m) isthe group of which the amino group of R^(il) is converted to theN-alkylamino group corresponding to the reactant carbonyl compound.

The reaction of Compound (1l) with a carbonyl compound is carried out,for example, in the presence of a reducing agent without using anysolvent or in a suitable solvent.

Examples of solvents that can be used include water; lower alcohols suchas methanol, ethanol, isopropanol, n-butanol, tert-butanol, and ethyleneglycol; acetonitrile; fatty acids such as formic acid and acetic acid;ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, anddiglyme; aromatic hydrocarbons such as benzene, toluene, and xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform, and carbon tetrachloride; and mixed solvents thereof.

Examples of reducing agents include fatty acids such as formic acid;fatty acid alkali metal salts such as sodium formate, and sodiumacetate; hydride reducing agents such as sodium borohydride, sodiumcyanoborohydride, and sodium triacetyloxyborohydride; mixtures of suchhydride reducing agents; catalytic hydrogenation reducing agents such aspalladium black, palladium carbon, platinum oxide, platinum black, andRaney nickel: and the like.

When a fatty acid such as formic acid, or a fatty acid alkali metal saltsuch as sodium formate or sodium acetate is used as the reducing agent,the reaction temperature is preferably room temperature to about 200°C., and preferably about 50° C. to about 150° C. The reaction usuallycompletes in about 10 minutes to about 10 hours. The amount of fattyacid or fatty acid alkali metal salt is preferably a large excessrelative to Compound (1l).

When a hydride reducing agent is used, the reaction temperature isusually about −80° C. to about 100° C., preferably about −80° C. toabout 70° C. The reaction usually completes in about 30 minutes to about60 hours. The amount of hydride reducing agent is usually about 1 toabout 20 moles, and preferably about 1 to about 6 moles, per mole ofCompound (1l).

Amines such as trimethylamine, triethylamine, andN-ethyldiisopropylamine, or molecular sieves such as molecular sieves 3A(MS-3A), and molecular sieves 4A (MS-4A) may be added to this reactionsystem.

When a catalytic hydrogen reducing agent is used, the reaction isusually carried out at normal pressure to about 20 atm, and preferablyat normal pressure to about 10 atm, in a hydrogen atmosphere or in thepresence of a hydrogen donor, such as formic acid, ammonium formate,cyclohexene, or enhydrous hydrazine. The reaction temperature is usuallyabout −30° C. to about 100° C., and preferably about 0° C. to about 60°C. The reaction usually completes in about 1 to about 12 hours. Theamount of catalytic hydrogen reducing agent is usually about 0.1 toabout 40 wt. %, and preferably about 1 to about 20 wt. %, relative toCompound (1l).

The amount of Compound (9) used in the reaction of Compound (1l) withCompound (9) is usually at least 1 mole, and preferably 1 mole to alarge excess, per mole of Compound (1l).

Among the benzazepine compounds represented by general formula (1) orsalts thereof, compounds wherein R¹ is —CO—(CH₂), and R⁴ is (4-3) alower alkoxycarbonyl group optionally substituted with a halogen atom, alower alkanoyloxy group, or 5-methyl-2-oxo-1,3-dioxol-4-yl can beprepared by reacting the compounds, wherein R⁴ is (4-1) a hydrogen atom,with an acid halide (10) by the process according to the followingReaction Scheme-12:

wherein R^(4b) is a lower alkoxycarbonyl group optionally substitutedwith a halogen atom, a lower alkanoyloxy group, or5-methyl-2-oxo-1,3-dioxol-4-yl, and R³, m, and X¹ are as defined above.

The reaction of Compound (1n) with an acid halide (10) is carried out ina suitable solvent in the presence of a basic compound.

The amount of acid halide (10) is usually 1 mole to a large excess, andpreferably 1 to 10 moles, per mole of Compound (1n).

Examples of reaction solvents include ethers such as diethyl ether,dioxane, tetrahydrofuran, monoglyme, and diglyme; halogenatedhydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane,and carbon tetrachloride; esters such as ethyl acetate; aromatichydrocarbons such as benzene, toluene, and xylene; aprotic polarsolvents such as acetonitrile, DMF, DMSO, and NMP; and mixed solventsthereof.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, and cesium carbonate; phosphates such as potassium phosphate,and sodium phosphate; and organic bases such as pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine, DBN, DBU, andDABCO.

The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (1n). Such anorganic base can also be used as the solvent.

When a catalyst such as 4-dimethylaminopyridine is present in thereaction system in the above reaction, the reaction can be promoted.

The reaction temperature of the above reaction is usually −10° C. to100° C., preferably 0° C. to 50° C., and more preferably 0° C. to roomtemperature. The reaction time is usually 15 minutes to 24 hours,preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours.

Among the benzazepine compounds represented by general formula (1) orsalts thereof, R¹ is a —CO—NHR⁴ group, and R⁴ is (4-2) a lower alkylgroup optionally substituted with a halogen atom, a lower alkylaminogroup, a lower alkoxycarbonyl group, or 5-methyl-2-oxo-1,3-dioxol-4-ylcan be prepared by reacting Compound (2) with an isocyanate compound(11) by the process according to Reaction Scheme-13.

wherein R^(4c) is a lower alkyl group optionally substituted with ahalogen atom, a lower alkylamino group, a lower alkoxycarbonyl group, or5-methyl-2-oxo-1,3-dioxol-4-yl.

The reaction of Compound (2) with Compound (11) is carried out in thepresence or absence of a basic compound, preferably in the absence of abasic compound, in a suitable inert solvent or without using anysolvent.

Examples of inert solvents include aromatic hydrocarbons such asbenzene, toluene, and xylene; ethers such as diethyl ether,tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform, and carbon tetrachloride; esters such as ethyl acetate, andmethyl acetate; ketones such as acetone, and methyl ethyl ketone;acetonitrile, pyridine, DMSO, DMF, hexamethylphosphoric triamide; andmixed solvents thereof.

Examples of basic compounds include triethylamine, pyridine, and thelike. The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mole of Compound (2). Such abasic compound can also be used as the solvent.

The amount of Compound (11) is usually about 1 to about 5 moles, andpreferably about 1 to 3 moles, per mole of Compound (2).

This reaction is usually carried out at about 0° C. to about 200° C.,and preferably about room temperature to about 150° C. The reactionusually completes in about 5 minutes to about 30 hours.

When a catalyst such as 4-dimethylaminopyridine is present in thereaction system in the above reaction, the reaction can be promoted.

Compounds (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (1b),(1b″), (1e), (1h), (1j), (1l), (1n), carboxylic acids, amine, andcarbonyl compound, which are used as starting materials in the aboveReaction Schemes, are known compounds, or compounds that can be easilyprepared according to known methods, such as the methods described inthe Examples below.

Compounds (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (1b),(1b″), (1e), (1h), (1j), (1l), (1n), carboxylic acids, amine, andcarbonyl compound, which are used as the starting materials in the aboveReaction Schemes, may be in the form of suitable salts or reactivederivatives thereof. Examples of such suitable salts include saltsmentioned above in Compound (1), such as sodium salts, potassium salts,cesium salts, and like alkali metal salts.

Compounds represented by general formula (1) of the present inventionand salts thereof include stereoisomers, optical isomers, and solvates(hydrates, ethanolates, etc.) thereof.

Among the benzazepine compounds represented by general formula (1) ofthe invention, compounds having a basic group can be easily convertedinto acid addition salts by reacting the compounds with pharmaceuticallyacceptable acids. Examples of such salts include inorganic acid saltssuch as hydrochloride, sulphate, phosphate, hydrobromate, hydriodate,and nitrate; organic acid salts such as acetate, oxalate, succinate,maleate, fumarate, malate, tartrate, citrate, malonate,methanesulfonate, benzoate, trifluoroacetate, benzensuplhonate, formate,and toluenesulfonate; and amino acid salts (for example, arginate,aspartate, glutamate, etc.).

Among the benzazepine compounds represented by general formula (1) ofthe invention, compounds having an acidic group can be easily convertedinto salts with a base by reacting the compounds with pharmaceuticallyacceptable basic compounds. Examples of such salts include metal saltssuch as alkali metal salts (for example, sodium salts, potassium salts,etc.) and alkaline earth metal salts (for example, calcium salts,magnesium salts, etc.); ammonium salts; organic base salts (for example,trimethylamine salts, triethylamine salts, pyridine salts, picolinesalts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts,tris(hydroxymethyl)aminomethane salts, etc.); and the like. Examples ofbasic compounds include sodium hydroxide, potassium hydroxide, calciumhydroxide, sodium carbonate, potassium hydrogen carbonate, sodiumhydrogen carbonate, and the like.

These salts are included in the scope of the present invention.

Each of the object compounds obtained according to the above ReactionSchemes can be isolated and purified from the reaction mixture by, forexample, after cooling, subjecting the reaction mixture to isolationprocedures such as filtration, concentration, extraction, etc., toseparate a crude reaction product followed by conventional purificationprocedures such as column chromatography, recrystallization, etc.

The compound of the present invention has, for example, vasopressinantagonism, vasodilatory activity, hypotensive activity, activity forinhibiting glucose release from the liver, mesangial cell growthinhibitory activity, aquaretic activity, and platelet aggregationinhibitory activity. The compound is useful as a vasodilator,hypotensor, aquaretic agent, and platelet aggregation inhibitor, and iseffective in the prevention and treatment of hypertension, edema (e.g.,cardiac edema, hepatic edema, renal edema, cerebral edema), abdominaldropsy, heart failure (e.g., severe heart failure), renal dysfunction,syndrome of inappropriate secretion of vasopressin (SIADH), livercirrhosis, hyponatremia, hypokalemia, diabetes, circulatoryinsufficiency, polycystic kidney disease (PKD), and the like.

When administered to the human body as a medicine, the compound of theinvention may be used simultaneously with or separately from otherpharmaceutical drugs, such as vasopressin antagonists, ACE inhibitors,β-blocking agents, aquaretic agents, angiotensin II antagonists (ARB),and/or digoxin.

The compound of the invention can be used in the form of a generalpharmaceutical composition. Such a pharmaceutical composition can beprepared by a conventional method using commonly used diluents and/orexcipients, such as fillers, extending agents, binders, humectants,disintegrators, surfactants, and lubricants.

The form of the pharmaceutical composition containing the compound ofthe invention can be suitably selected depending on the purpose of thetreatment. Examples thereof include tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, suppositories, injections(solutions, suspensions, etc.), ointments, and the like.

To form tablets, any of the various carriers conventionally known inthis field can be widely used. Examples thereof include excipients suchas lactose, white sugar, sodium chloride, glucose, urea, starch, calciumcarbonate, kaolin, crystalline cellulose, and silicic acid; binders suchas water, ethanol, propanol, simple syrup, glucose solutions, starchsolutions, gelatin solutions, carboxymethylcellulose, shellac,methylcellulose, potassium phosphate, and polyvinylpyrrolidone;disintegrators such as dry starch, sodium alginate, agar powder,laminaran powder, sodium hydrogen carbonate, calcium carbonate, fattyacid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, stearicacid monoglycerides, starch, and lactose; disintegration inhibitors suchas white sugar, stearin, cacao butter, and hydrogenated oils; absorbingagents such as quaternary ammonium bases, and sodium lauryl sulfate;wetting agents such as glycerol, and starch; adsorbents such as starch,lactose, kaolin, bentonite, and colloidal silicic acid; lubricants suchas purified talc, stearates, boric acid powder, and polyethylene glycol;and the like. Further, such tablets may be tablets provided with typicalcoating as required, for example, sugar-coated tablets, gelatinencapsulated tablets, enteric-coated tablets, film-coated tablets,double- or multi-layered tablets, etc.

To form pills, any of the various carriers conventionally known in thisfield can be widely used. Examples thereof include excipients such asglucose, lactose, starch, cacao butter, hydrogenated vegetable oils,kaolin, and talc; binders such as gum arabic powder, tragacanth powder,gelatin, and ethanol; disintegrators such as laminarin, and agar; andthe like.

To form suppositories, any of the various carriers conventionally knownin this field can be widely used. Examples thereof include polyethyleneglycol, cacao butter, higher alcohols, esters of higher alcohols,gelatin, semi synthetic glycerides, and the like.

Capsules can be prepared according to a conventional method by mixingthe active ingredient compound with various carriers as mentioned aboveand filling the mixture into a hard gelatin capsule, soft gelatincapsule, or the like.

To form injections, solutions, emulsions, and suspensions are preferablysterilized and isotonic to the blood. When injections are prepared inthe form of solutions, emulsions and suspensions, any of the diluentscommonly employed in this field can be used. Examples of such diluentsinclude water, aqueous lactic acid solutions, ethyl alcohol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,polyoxyethylene sorbitan fatty acid esters, and the like. In this case,isotonizing agents such as sodium chloride, glucose, mannitol, andglycerol in an amount sufficient to prepare an isotonic solution may beincorporated into the pharmaceutical composition. Commonly used pHadjusters, solubilizers, buffers, smoothing agents, and the like mayalso be added.

Other additives such as coloring agents, preservatives, flavors, andsweetening agents, and other medicines can also be added, if necessary.

The amount of compound represented by general formula (1) or saltthereof in the pharmaceutical preparation of the invention is notparticularly limited, and can be suitably selected from a wide range. Ingeneral, the proportion of the compound is preferably about 0.01 toabout 70 wt. % of the pharmaceutical preparation.

The way of administration of the pharmaceutical preparation of theinvention is not particularly limited, and can be administered by amethod suitable to the form of the preparation, the patient's age, sexand other conditions, and the severity of the disease. For example,tablets, pills, solutions, suspensions, emulsions, granules, andcapsules are administered orally. Injections are intravenouslyadministered singly or as mixed with typical replacement fluid such asglucose solutions, amino acid solutions, or the like, or singlyadministered intramuscularly, intracutaneously, subcutaneously orintraperitoneally, as required.

The dosage of the pharmaceutical preparation of the invention issuitably selected according to the dosage regimen, the patient's age,sex and other conditions, and the severity of the disease. The dosage isusually such that the compound represented by general formula (1), whichis an effective ingredient, is administered in an amount of 0.001 to 100mg, and preferably 0.001 to 50 mg, per kg of body weight per day in oneor more administrations.

The dosage varies with various conditions. A dosage smaller than theabove range may be sufficient, while a dosage larger than the aboverange may be necessary.

The patents, patent applications, and documents cited herein areincorporated by reference.

EFFECT OF THE INVENTION

According to the present invention, a novel benzazepine compound thathas excellent properties, such as the maintenance of the blood level oftolvaptan for a long period of time enabling to provide the desiredpharmaceutical effects, can be provided.

When administered into the human body, Compound (1) of the invention ora salt thereof can be easily converted into tolvaptan, which is anactive ingredient.

Further, Compound (1) of the invention or a salt thereof is readilycrystallized and easy to handle. Furthermore, Compound (1) of theinvention or a salt thereof has excellent chemical stability.

A composition that can provide pharmaceutical effects equivalent to thatof a useful drug tolvaptan can be provided in various forms by usingCompound (1) of the invention or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples illustrate the present invention in furtherdetail.

Example 1{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

Tolvaptan (1.0 g, 2.2 mmol), succinic anhydride (0.33 g, 3.3 mmol), and4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added to1-methyl-2-pyrolidone (3 ml), and the mixture was stirred at 100° C. for1 hour. Water was added to the reaction mixture, and the resultedprecipitates were collected by filtration. The precipitates werepurified using silica gel flash chromatography (n-hexane:ethylacetate=50:50→20:80). The purified product was concentrated underreduced pressure. The residue was dissolved in aqueous acetonitrile, andthen freeze-dried to obtain 300 mg of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.1 (4H, m), 2.37 (6H, s), 2.5-2.6 (2H, m), 2.6-2.7 (2H, m), 3.0-4.3(2H, m), 5.9-6.0 (1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m), 7.3-7.5 (4H,m), 7.56 (1H, s), 9.8 (1H, br).

Example 2 Sodium{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

A sodium hydrogen carbonate (46 mg, 0.55 mmol) aqueous solution (2 ml)was added to a methanol solution (2 ml) of{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate(0.30 g, 0.55 mmol), and the mixture was stirred at room temperature for1 hour. Methanol was distilled off under reduced pressure at about 30°C. The resulting solution was freeze-dried to obtain 0.29 g (94%) ofsodium{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinateas amorphous.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.70-2.10 (4H, m), 2.19 (2H, t, J=7.1 Hz), 2.37 (6H, s), 2.56 (2H, t,J=7.1 Hz), 3.05-3.50 (1H, m), 3.65-4.25 (1H, m), 5.85-5.95 (1H, m),6.75-6.90 (1H, m), 6.90-7.10 (2H, m), 7.15-7.55 (6H, m), 7.58 (1H, s),9.80 (1H, br).

Example 3 Potassium{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

Amorphous of potassium{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinatewas obtained in a similar manner as in the above Example 2.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.70-2.10 (4H, m), 2.16 (2H, t, J=7.1 Hz), 2.37 (6H, s), 2.48 (2H, t,J=7.1 Hz), 2.95-3.50 (1H, m), 3.70-4.25 (1H, m), 5.85-5.95 (1H, m),6.75-6.90 (1H, m), 7.00-7.15 (2H, m), 7.20-7.45 (6H, m), 7.58 (1H, s),9.77 (1H, br).

Example 4 Sodium4-{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonyl}butyrate

4-{7-Chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonyl}butyricacid (0.30 g, 0.53 mmol) was dissolved in acetone (2 ml). A sodiumhydrogen carbonate (45 mg, 0.53 mmol) aqueous solution (2 ml) was addedthereto and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was concentrated, and the residue was washed with ethylacetate and then air-dried to obtain 0.14 g (45%) of sodium4-{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonyl}butyrateas amorphous.

¹H-NMR (DMSO-d₅, 100° C.) δ ppm:

1.70-2.10 (8H, m), 2.37 (6H, s), 2.45-2.55 (2H, m), 3.10-3.55 (1H, m),3.70-4.10 (1H, m), 5.90-6.00 (1H, m), 6.85-6.95 (1H, m), 7.00-7.10 (1H,m), 7.10-7.45 (7H, m), 7.58 (1H, s), 9.83 (1H, br).

Example 5{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}methylsuccinate

Iodomethane (34 μl, 0.55 mmol) was added to a DMF (5 ml) suspension of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate(0.25 g, 0.46 mmol) and potassium carbonate (76 mg, 0.55 mmol), and themixture was stirred at room temperature for 2 hours. Water was thenadded to the reaction mixture, and the resulted precipitates werecollected by filtration and air-dried. The dried product was purified bysilica gel chromatography (n-hexane:ethyl acetate). The purified productwas crystallized from methanol/water to thereby obtain 0.20 g (77%) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}methylsuccinate as white powder.

Melting point: 173.6-175.5° C.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.70-2.05 (4H, m), 2.37 (6H, s), 2.55-2.70 (2H, m), 2.70-2.80 (2H, m),3.10-3.45 (1H, m), 3.62 (3H, s), 3.80-4.10 (1H, m), 5.90-6.00 (1H, m),6.80-7.00 (2H, m), 7.05-7.25 (3H, m), 7.30-7.45 (4H, m), 7.56 (1H, s),9.79 (1H, br).

Example 67-Chloro-5-[N-(2-hydroxy-ethyl)-succinamoyloxy]-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine

{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate(0.30 g, 0.55 mmol), 2-aminoethanol (40 μl, 0.66 mmol), WSC (0.13 g,0.66 mmol), and 1-hydroxybenzotriazole (HOBt) (0.10 g, 0.66 mmol) weredissolved in DMF (5 ml), and the mixture was stirred out at roomtemperature over night. Water was then added to the reaction mixture.The resulted precipitates were collected by filtration and air-dried.The dried product was purified by basic silica gel chromatography (ethylacetate: methanol) to thereby obtain 0.19 g (59%) of7-chloro-5-[N-(2-hydroxy-ethyl)-succinamoyloxy]-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepineas amorphous.

¹H-NMR (CDCl₃) δ ppm:

1.25-2.90 (12H, m), 2.95-3.75 (7H, m), 4.60-4.95 (1H, m), 5.80-6.05 (1H,m), 6.35-6.65 (2H, m), 6.80-7.05 (2H, m), 7.10-7.70 (8H, m), 8.00-8.25(1H, m).

Example 7{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio}aceticacid (also known as: tolvaptan thiodiglycolic acid monoester)

Tolvaptan (1.0 g, 2.2 mmol) and 4-dimethylaminopyridine (27 mg, 0.22mmol) were dissolved in pyridine (5 ml). Thiodiglycolic anhydride (2.9g, 22 mmol) was added thereto, and the mixture was stirred at roomtemperature for 1 hour. 1N hydrochloric acid was added to the reactionmixture, and then the mixture was extracted with ethyl acetate. Theorganic layer was washed with 1N hydrochloric acid, dried over anhydroussodium sulfate. After filtration and concentration under reducedpressure, the residue was purified by silica gel flash chromatography(dichloromethane:methanol=100:0→83:17), and the colored component wasremoved by silica gel column chromatography (ethyl acetate). Theresultant was further purified by silica gel flash chromatography(n-hexane:ethyl acetate=50:50→0:100), and the purified product wasconcentrated under reduced pressure. The residue was dissolved inaqueous acetonitrile, and then freeze-dried to obtain 350 mg of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio}aceticacid as white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.2 (4H, m), 2.4 (6H, s), 3.0-4.4 (2H, m), 3.39 (2H, s), 3.60 (2H,s), 5.8-6.0 (1H, m), 6.8-7.1 (2H, m), 7.2-7.5 (7H, m), 7.57 (1H, s), 9.8(1H, br).

Example 8 Methyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio}-acetate

Tolvaptan (1.0 g, 2.2 mmol) and 4-dimethylaminopyridine (27 mg, 0.22mmol) were dissolved in pyridine (5 ml). Thiodiglycolic anhydride (0.43g, 3.3 mmol) was added thereto, and the mixture was stirred at roomtemperature over night. Thiodiglycolic anhydride (0.86 g, 6.5 mmol) wasfurther added, and then the mixture was stirred at room temperature for2 hours. 1N hydrochloric acid was added to the reaction mixture, thenthe mixture was extracted with ethyl acetate. The organic layer waswashed with 1N hydrochloric acid, dried over anhydrous sodium sulfate.After filtration and concentration under reduced pressure,trimethylsilyldiazomethane was added to the residue, and the mixture wasstirred at room temperature for 1 hour. The resultant mixture wasfurther concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=60:40→0:100). The purified product was concentrated underreduced pressure, the residue was dissolved in aqueous acetonitrile andthen freeze-dried to obtain 880 mg of methyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio}-acetateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.5-1.9 (4H, m), 2.37 (6H, s), 2.8-4.3 (2H, m), 3.48 (2H, s), 3.61 (2H,s), 3.63 (3H, s), 5.9-6.1 (1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m),7.3-7.5 (4H, m), 7.57 (1H, s), 9.82 (1H, br).

Example 9 Methyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylsulfonyl}-acetate

Methyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio}-acetate(480 mg, 0.81 mmol) was dissolved in a methanol (5 ml) and water (2 ml).Oxone® (2KHSO₅/K₂SO₄/KHSO₄) (1.5 g, 2.4 mmol) was added thereto and themixture was stirred at room temperature for 20 hours. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate. After filtrationand concentration under reduced pressure, the residue was purified bysilica gel flash chromatography (n-hexane:ethyl acetate=50:50→20:80).The purified product was concentrated under reduced pressure, theresidue was dissolved in aqueous acetonitrile and freeze-dried to obtain200 mg of methyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylsulfonyl}-acetateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.5-1.9 (4H, m), 2.37 (6H, s), 2.8-4.3 (2H, m), 3.48 (2H, s), 3.61 (2H,s), 3.63 (3H, s), 5.9-6.1 (1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m),7.3-7.5 (4H, m), 7.57 (1H, s), 9.82 (1H, br).

Example 10{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}hexadecanoate

Palmitoyl chloride (1.24 ml, 4.4 mmol) was added to a dichloromethane(20 ml) solution of tolvaptan (2.00 g, 4.4 mmol) and pyridine (0.40 ml,5.0 mmol), and the mixture was stirred at room temperature over night.Water was added to the reaction mixture and the mixture was extractedwith dichloromethane. The combined organic layer was washed with waterand an aqueous saturated sodium chloride solution, and dried overmagnesium sulfate. After filtration and concentration, the residue waspurified by silica gel chromatography (n-hexane:ethyl acetate) tothereby obtain 2.25 g (74%) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}hexadecanoateas amorphous.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

0.85 (3H, t, J=6.8 Hz), 1.15-1.45 (24H, m), 1.55-1.70 (2H, m), 1.75-2.10(4H, m), 2.37 (6H, s), 2.40-2.50 (2H, m), 3.05-3.55 (1H, m), 3.60-4.30(1H, m), 5.90-6.00 (1H, m), 6.80-7.05 (2H, m), 7.10-7.45 (7H, m), 7.56(1H, s), 9.81 (1H, br).

Example 11{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}chloroacetate

Tolvaptan (10 g, 22 mmol) and pyridine (2.7 ml, 33 mmol) were suspendedin dichloromethane (100 ml), and chloroacetyl chloride (2.6 ml, 33 mmol)was added dropwise under cooling with ice. The obtained mixture wasstirred at room temperature for 1 hour. 1N hydrochloric acid was addedto the reaction mixture, and the mixture was extracted withdichloromethane. The organic layer was washed with 1N hydrochloric acid,dried over anhydrous sodium sulfate. After filtration and concentrationunder reduced pressure, the residue was purified by silica gel flashchromatography (n-hexane:ethyl acetate=60:40→46:54). The purifiedproduct was concentrated under reduced pressure to obtain 12g of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}chloroacetateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.7-2.2 (4H, m), 2.36 (6H, s), 2.6-4.3 (2H, m), 4.44 (2H, s), 5.9-6.0(1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m), 7.3-7.5 (4H, m), 7.57 (1H,s), 9.8 (1H, br).

Example 12 tert-Butyl4-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine-1-carboxylate

{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}chloroacetate(1.2 g, 2.3 mmol), tert-butyl piperazine-1-carboxylate(1-BOC-piperazine) (0.47 g, 2.5 mmol), and potassium carbonate (0.35 g,2.5 mmol) were added to acetonitrile (10 ml), and the mixture wasstirred at room temperature for 2 hours. Ethyl acetate was then added tothe reaction mixture and the insoluble substance was removed byfiltration. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel flash chromatography(n-hexane:ethyl acetate=50:50→20:80). The purified product wasconcentrated under reduced pressure to obtain 1.2 g of tert-butyl4-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine-1-carboxylateas yellow oil.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.42 (9H, s), 1.7-2.2 (4H, m), 2.39 (6H, s), 2.56 (4H, t, J=5.1 Hz),3.37 (4H, t, J=5.1 Hz), 3.42 (2H, s), 2.6-4.3 (2H, m), 5.9-6.1 (1H, m),6.9-7.0 (1H, m), 7.0-7.1 (1H, m), 7.1-7.5 (7H, m), 7.59 (1H, s), 9.8(1H, br).

Example 131-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazinedihydrochloride

A 4N hydrogen chloride ethyl acetate solution (3.7 ml) was added to anethyl acetate solution (15 ml) of tert-butyl4-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine-1-carboxylate(1.2 g, 1.8 mmol), and the mixture was stirred at room temperature for12 hours. The precipitates were collected by filtration, washed withethyl acetate, and dried to obtain 800 mg of1-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazinedihydrochloride as yellow powder.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.4 (4H, m), 2.369 (3H, s), 2.374 (3H, s), 2.8-3.0 (4H, m), 3.0-3.2(4H, m), 3.4-3.7 (2H, m), 3.0-4.3 (2H, m), 5.7 (1H, br), 5.9-6.1 (1H,m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m), 7.3-7.5 (4H, m), 7.56 (1H, s), 9.2(2H, br), 9.87 (1H, br).

Example 141-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-4-methyl-piperazinedihidrochloride

1-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazinedihydrochloride (400 mg, 0.62 mmol), formalin (0.15 ml, 1.9 mmol),sodium acetate (61 mg, 0.74 mmol), and sodium cyanotrihydroborate (119mg, 1.9 mmol) were added to methanol (5 ml), and the mixture was stirredat room temperature for 1 hour. Water and aqueous sodium hydroxidesolution were added to the reaction mixture, and the precipitates werecollected by filtration, washed with water, and then dried. The obtainedsolid was dissolved in ethyl acetate, and a 4N hydrogen chloride ethylacetate solution (0.5 ml) was added thereto. The precipitates were thencollected by filtration, washed with ethyl acetate and dried to obtain240 mg of1-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-4-methyl-piperazinedihydrochloride as white powder.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.1 (4H, m), 2.369 (3H, s), 2.374 (3H, s), 2.73 (3H, s), 2.8-4.3(2H, m), 2.8-3.0 (4H, m), 3.0-3.4 (4H, m), 3.54 (2H, s), 5.9-6.1 (1H,m), 6.8-7.1 (2H, m), 7.1-7.4 (7H, m), 7.54 (1H, s), 9.8 (1H, br).

Example 15{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}-4-dimethylaminobutyratehydrochloride

Tolvaptan (1.0 g, 2.2 mmol), 4-dimethylamino-butyric acid hydrochloride(0.48 g, 2.9 mmol), and 4-dimethylaminopyridine (27 mg, 0.22 mmol) weresuspended in dichloromethane (5 ml). Triethylamine (0.4 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.55g, 2.9 mmol) were added thereto, and the mixture was stirred at roomtemperature for 12 hours. An aqueous saturated sodium hydrogen carbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with anaqueous saturated sodium chloride solution, dried over anhydrous sodiumsulfate. After filtration and concentration under reduced pressure, theresidue was purified by silica gel flash chromatography (n-hexane:ethylacetate=50:50→0:100). The purified product was concentrated underreduced pressure. The residue was then dissolved in ethyl acetate, a 4Nhydrogen chloride ethyl acetate solution was added thereto, and theresultant mixture was concentrated under reduced pressure. To theresidue was added water (10 ml). After filteration, the filtrate wasfreeze-dried to obtain 0.91 g of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-dimethylaminobutyrate hydrochloride as white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.1 (6H, m), 2.37 (3H, s), 2.38 (3H, s), 2.5-2.6 (2H, m), 2.74 (6H,s), 3.0-3.1 (2H, m), 3.0-4.3 (2H, m), 5.9-6.0 (1H, m), 6.7-7.1 (2H, m),7.1-7.2 (3H, m), 7.2-7.5 (4H, m), 7.54 (1H, s), 9.8 (1H, br).

Example 167-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-chlorobutyrate

Tolvaptan (10.0 g, 22.3 mmol) was dispersed in dichloromethane (100 ml).Pyridine (2.7 ml) was added thereto, and the mixture was stirred.4-Chlorobutyric acid chloride (3.74 ml) was gradually added to theobtained mixture, and the mixture was stirred at room temperature overnight. The reactant was then poured into water, and the mixture wasextracted with dichloromethane, washed with a sodium hydrogen sulfateaqueous solution, dried over magnesium sulfate. After filtration andconcentration under reduced pressure, the resulted residue wascrystallized with diethyl ether. The resulted crystals were collected byfiltration, and dried to obtain 10.7 g of7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-chlorobutyrate as white powder.

¹H-NMR (CDCl₃) δ ppm:

1.50-2.92 (16H, m), 3.10-4.02 (2.4H, m), 4.70-5.13 (1H, m), 5.86-6.19(1.2H, m), 6.48-6.68 (1H, m), 6.82-7.82 (8.8H, m).

Example 177-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-(4-acetylpiperazin-1-yl)butyrate

7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-chlorobutyrate (0.5 g) was dissolved in acetonitrile (10 ml).1-Acetylpiperazine (0.35 g), sodium iodide (0.41 g), and sodiumcarbonate (0.19 g) were added to the solution, and the mixture washeated under reflux for 19 hours. The reactant was poured into water,and the mixture was extracted with ethyl acetate, washed with water,dried over sodium carbonate. After filtration and concentration underreduced pressure, the residue was purified by silica gel columnchromatography (dichloromethane:methanol=100:1→100:10) to obtain 0.3 gof7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl4-(4-acetylpiperazin-1-yl)butyrate as colorless oil.

¹H-NMR (CDCl₃) δ ppm:

1.52-2.66 (23.6H, m), 2.70-2.92 (1H, m), 3.03-4.07 (4.4H, m), 4.72-5.14(1H, m), 5.83-6.20 (1.2H, m), 6.45-6.68 (1H, m), 6.79-7.78 (8.8H, m).

Example 187-Chloro-1-[2-methyl-4-(2-methylbenzamido)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl[(1-chloroethoxycarbonyl)methylamino]acetate

1-Chloroethyl chloroformate (0.12 ml, 1.2 mmol) was added dropwise to adichloromethane (10 ml) solution of7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ylmethylaminoacetate (0.60 g, 1.2 mmol), and the mixture was cooled withice. Then N-methylmorpholine (0.15 ml, 1.4 mmol) was gradually addeddropwise thereto. After the resultant mixture was stirred at roomtemperature for 1 hour, the reaction mixture was diluted with ethylacetate, washed with water and an aqueous saturated sodium chloridesolution, dried over sodium sulfate. After filtration and concentration,the residue was purified by silica gel chromatography (n-hexane:ethylacetate) to obtain 0.67 g (93%) of7-chloro-1-[2-methyl-4-(2-methylbenzamido)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl[(1-chloroethoxycarbonyl)methylamino]acetate as amorphous.

¹H-NMR (CDCl₃) δ ppm:

1.70-1.95 (5H, m), 2.10-2.55 (7H, m), 2.75-3.15 (4H, m), 3.85-4.55 (2H,m), 4.70-5.10 (1H, m), 5.85-6.20 (1H, m), 6.45-6.65 (2H, m), 6.75-7.75(11H, m)

MS (M⁺¹): 626.

Example 197-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl[(1-acetoxy-ethoxycarbonyl)methylamino]actate

N-methylmorpholine (0.31 ml, 2.8 mmol) was added dropwise to an aceticacid (0.32 ml, 5.6 mmol) solution of7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl[(1-chloroethoxycarbonyl)methylamino]acetate (0.35 g, 0.56 mmol) undercooling with ice, and the mixture was stirred at room temperature fortwo days. Water was added to the reaction mixture, and then the resultedprecipitates were collected by filtration and air-dried. The driedproduct was purified by silica gel chromatography (n-hexane:ethylacetate) to obtain 0.26 g (72%) of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl[(1-acetoxy-ethoxycarbonyl)methylamino]acetate as amorphous.

¹H-NMR (DMSO-d₆) δ ppm:

1.35-1.45 (3H, m), 1.75-2.15 (7H, m), 2.37 (6H, s), 2.95 (3H, s),3.15-3.50 (1H, m), 3.70-4.15 (1H, m), 4.17 (2H, s), 5.95-6.05 (1H, m),6.55-6.70 (1H, m), 6.85-7.00 (2H, m), 7.10-7.25 (3H, m), 7.30-7.45 (4H,m), 7.56 (1H, s), 9.77 (1H, br).

Example 207-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate

Tolvaptan (0.63 g),3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyricacid (0.70 g), and 4-dimethylaminopyridine (DMAP) (24 mg, 0.22 mmol)were suspended in dichloromethane (10 ml).N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (WSC) (383 mg) was added thereto, and the mixture wasstirred at room temperature for 3 hours. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, dried overanhydrous sodium sulfate. After filtration and concentration underreduced pressure, the residue was purified by silica gel flashchromatography (n-hexane:ethyl acetate=70:30→35:65). The purifiedproduct was concentrated under reduced pressure to obtain 0.92 g of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.5-1.9 (7H, m), 2.10 (3H, s), 2.32 (3H, s), 2.36 (3H, s), 2.6-4.3 (2H,m), 2.91 (2H, d, J=15.3 Hz), 3.13 (2H, d, J=15.3 Hz), 5.11 (2H, s), 5.14(2H, s), 5.7-5.9 (1H, m), 6.74 (1H, s), 6.75-7.4 (20H, m), 7.54 (1H, s),9.8 (1H, br).

Example 217-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl3-(2,4-dimethyl-6-phosphonooxy-phenyl)-3-methyl-butyrate

A mixture of7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate(0.92 g) in ethyl acetate (10 ml) was hydrogenated over 5% platinumcarbon (100 mg). The catalyst was removed by filtration through Celitelayer, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography(dichloromethane:methanol=90:10→50:50). The purified product wasconcentrated under reduced pressure, and the aqueous acetonitrilesolution of the residue was freeze-dried to obtain 0.21 g of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl3-(2,4-dimethyl-6-phosphonooxy-phenyl)-3-methyl-butyrate as whiteamorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.60 (3H, s), 1.61 (3H, s), 1.6-2.0 (4H, m), 2.10 (3H, s), 2.34 (3H, s),2.37 (3H, s), 2.42 (3H, s), 2.3-4.2 (2H, m), 2.9-3.4 (2H, m), 5.8-5.9(1H, m), 6.45 (1H, s), 6.8-6.9 (1H, m), 6.9-7.0 (1H, s), 7.0-7.4 (7H,m), 7.43 (1H, d, J=7.4 Hz), 7.63 (s, 3H), 9.91 (1H, br).

Example 22 Chloromethyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}carbonate

Tolvaptan (5.0 g) and pyridine (1.1 ml) were suspended indichloromethane (50 ml). Chloromethyl chloroformate (1.1 ml) was addedthereto under cooling with ice, and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was washed with water,dried over anhydrous sodium sulfate. After filtration and concentrationunder reduced pressure, the residue was purified by silica gel flashchromatography (n-hexane:ethyl acetate=70:30→50:50). The purifiedproduct was concentrated under reduced pressure to obtain 6.1 g ofchloromethyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}carbonateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.7-2.2 (4H, m), 2.36 (6H, s), 2.6-5.8 (2H, m), 5.9-6.0 (3H, m), 6.8-7.1(2H, m), 7.1-7.5 (7H, m), 7.58 (1H, s), 9.8 (1H, br).

Example 23{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}iodomethylcarbonate

Chloromethyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}carbonate(3.8 g) and sodium iodide (5.3 g) were added to acetone (27 ml), andthen the mixture was heated under reflux for 3 hours. After cooling toroom temperature, water was added thereto and the resulted precipitateswere collected by filtration. The precipitates were washed with water,and dried to obtain 4.2 g of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}iodomethylcarbonate as slightly yellow powder.

¹H-NMR (toluene-d₈, 100° C.) δ ppm:

1.3-1.8 (4H, m), 2.31 (3H, s), 2.42 (3H, s), 2.7-4.3 (2H, m), 5.48 (2H,d, J=5.1 Hz), 5.53 (2H, d, J=5.1 Hz), 5.5 (1H, m), 6.4-6.8 (3H, m),6.8-7.2 (6H, m), 7.2 (1H, m), 7.36 (1H, s).

Example 24 Acetoxymethyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}carbonate

Sodium acetate (300 mg) was added to an acetonitrile solution (5 ml) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}iodomethylcarbonate, and then the mixture was heated under reflux for 8 hours. Thereaction mixture was cooled to room temperature and the insolublesubstance was removed by filtration. The filtrate was concentrated underreduced pressure and the residue was purified by silica gel flashchromatography (n-hexane:ethyl acetate=71:29→30:70). The purifiedproduct was concentrated under reduced pressure. The aqueousacetonitrile solution of the residue was freeze-dried to obtain 6.1 g ofacetoxymethyl{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}carbonateas white amorphous solid.

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.3-1.8 (4H, m), 1.6 (3H, s), 2.3(3H, s), 2.4 (3H, s), 2.7-4.4 (2H, m), 5.6 (2H, dd, J=5.5 Hz, 10.4 Hz),5.6-5.9 (1H, m), 6.5 (1H, d, J=8.4 Hz), 6.6 (1H, br), 6.7 (1H, dd,J=2.3, 8.4 Hz), 6.8-7.2 (5H, m), 7.3 (1H, d, J=2.1 Hz), 7.4 (1H, 1.6 Hz)

Example 257-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine

Dimethylsulfoxide (DMSO) (3 ml), acetic anhydride (1.5 ml), and aceticacid (1.5 ml) were added to tolvaptan (1.0 g, 2.2 mmol), and the mixturewas stirred at 70° C. for 4 hours. Water and 1N aqueous sodium hydroxidesolution were added to the reaction mixture, and the mixture wasextracted with ethyl acetate, washed with an aqueous saturated sodiumchloride solution, dried over anhydrous sodium sulfate. After filtrationand concentration under reduced pressure, the residue was purified bysilica gel flash chromatography (n-hexane:ethyl acetate=80:20→20:80).The purified product was concentrated under reduced pressure to obtain0.62 g of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepineas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.7-2.2 (4H, m), 2.17 (3H, s), 2.36 (6H, s), 2.6-4.3 (2H, m), 4.70 (2H,d, J=11.2 Hz), 4.83 (2H, d, J=11.2 Hz), 4.9 (1H, m), 6.7-7.0 (1H, m),7.0-7.5 (8H, m), 7.56 (1H, s), 9.8 (1H, br).

Example 26{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxymethyl}dihydrogenphosphate

7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine(509 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (10 ml). Sulfuricchloride (0.12 ml, 1.5 mmol) was added thereto, and the mixture wasstirred at room temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure. Acetonitrile (10 ml), formic acid(0.68 ml, 10 mmol), and triethylamine (1.4 ml, 10 mmol) were added tothe residue, and the mixture was stirred at 70° C. for 30 minutes. Aftercooling to room temperature, water was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was extracted withan aqueous saturated sodium hydrogen carbonate solution twice. Citricacid was gradually added to the aqueous layer until no foam wasobserved, and the aqueous layer was extracted with dichloromethanetwice. The combined organic layer was dried over anhydrous sodiumsulfate. After filtration and concentration under reduced pressure, theresidue was dissolved in ethyl acetate under heating, and the insolublesubstance was removed by filtration while it is hot. After cooling thefiltrate, the resulted precipitates were collected by filtration anddried to obtain 180 mg of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxymethyl}dihydrogenphosphate as white powder.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.2 (4H, m), 2.3-2.4 (6H, m), 2.8-4.3 (2H, m), 4.9-5.2 (2H, m),5.2-5.3 (1H, m), 6.7-7.7 (10H, m), 9.81 (1H, br).

Example 275-Acetoxymethoxy-7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine

7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine(509 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (10 ml). Sulfuricchloride (0.12 ml, 1.5 mmol) was added thereto, and the mixture wasstirred at room temperature for 15 minutes. The obtained mixture wasconcentrated under reduced pressure, and acetonitrile (10 ml), sodiumacetate (246 mg, 2.0 mmol), and sodium iodide (450 mg, 3.0 mmol) wereadded to the residue, and then the mixture was heated under reflux for 1hour. After cooling to room temperature, ethyl acetate was addedthereto, and the insoluble subject was removed by filtration. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel flash chromatography (n-hexane:ethylacetate=65:35→50:50). The purified product was concentrated underreduced pressure, and the residue was dissolved in aqueous acetonitrile.After concentration at room temperature under reduced pressure, theresulted precipitates were collected by filtration, and dried to obtain280 mg of5-acetoxymethoxy-7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepineas white powder.

¹H-NMR (toluene-d_(g), 100° C.) δ ppm:

1.3-1.9 (7H, m), 2.32 (3H, s), 2.41 (3H, s), 2.8-4.1 (2H, m), 4.6-4.8(1H, m), 5.17 (2H, s), 6.4-6.8 (3H, m), 6.8-7.3 (6H, m), 7.39 (1H, s).

Example 28{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate

Tolvaptan (1.0 g, 2.2 mmol) was suspended in toluene (7 ml).2-Chloroethyl isocyanate (0.28 ml, 3.3 mmol) and 4-dimethylaminopyridine(DMAP) (27 mg, 0.22 mmol) were added thereto, and the mixture wasstirred at 80° C. for 24 hours. After cooling to room temperature, theinsoluble materials were filtered off and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography (n-hexane:ethylacetate=54:46→33:67). The purified product was concentrated underreduced pressure to obtain 1.0 g of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamateas white amorphous solid.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.2 (4H, m), 2.36 (6H, s), 2.6-4.3 (2H, m), 3.42 (2H, t, J=6.0 Hz),3.64 (2H, dd, J=6.0, 12.1 Hz), 5.8-5.9 (3H, m), 6.7-7.5 (10H, m), 7.56(1H, s), 9.8 (1H, br).

Example 29(2-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylamino}-ethyl)-trimethyl-ammoniumchloride

Trimethylamine (30% solution, 0.5 ml) was added to an ethanol solution(10 ml) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethy)carbamate(330 mg), and the mixture was heated at 170° C. for 15 minutes(microwave reactor). After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. To the residue wasadded ethyl acetate, and the resulted precipitates were collected byfiltration and dried to obtain 120 mg of(2-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylamino}-ethyl)-trimethyl-ammoniumchloride as white powder.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.6-2.2 (4H, m), 2.34 (3H, s), 2.37 (3H, s), 2.8-4.3 (2H, m), 3.1-3.9(9H, m), 3.3-3.7 (5H, m), 5.8-6.0 (1H, m), 6.7-7.1 (2H, m), 7.1-7.5 (7H,m), 7.56 (1H, s), 9.88 (1H, br).

Example 30{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}2,2-dimethyl-propionyloxymethylsuccinate

Amorphous of{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}2,2-dimethyl-propionyloxymethylsuccinate was prepared in a similar manner as in the above Example 5.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.14 (9H, s), 1.75-2.10 (4H, m), 2.37 (6H, s), 2.65-2.80 (4H, m),3.10-3.55 (1H, m), 3.65-4.15 (1H, m), 5.71 (2H, s), 5.85-6.00 (1H, m),6.85-7.05 (2H, m), 7.10-7.25 (3H, m), 7.30-7.45 (4H, m), 7.55 (1H, s),9.76 (1H, br).

Example 31{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(ethoxycarbonylmethyl-methyl-carbamoyloxy)acetate

{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}chloroacetate(500 mg, 0.95 mmol), ethyl sarcosinate hydrochloride (230 mg, 1.5 mmol),and potassium carbonate (414 mg, 3.0 mmol) were added todimethylformamide (DMF) (5 ml), and the mixture was stirred at 60° C.for 1 hour. Water was added to the reaction mixture, and the resultedprecipitates were collected by filtration and washed with water. Theprecipitates were dissolved in ethyl acetate, dried over anhydroussodium sulfate, filtrated and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography (n-hexane:ethylacetate=36:64→15:85). The purified product was concentrated underreduced pressure. Water was added the residue, and resulted precipitateswere collected by filtration and dried to obtain 330 mg of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(ethoxycarbonylmethyl-methyl-carbamoyloxy)acetateas white powder.

¹H-NMR (DMSO-d₆) δ ppm:

1.19 (3H, t, J=7.1 Hz), 1.6-2.2 (4H, m), 2.37 (6H, s), 2.8-4.3 (2H, m),2.85 (2H, s), 2.96 (3H, s), 4.04 (2H, s), 4.13 (2H, q, J=7.1 Hz), 4.75(2H, s), 5.9-6.1 (1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (3H, m), 7.3-7.5 (4H,m), 7.56 (1H, s), 9.80 (1H, br).

Example 32{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methoxycarbonyl)-amino]acetate

7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ylmethylaminoacetate (0.34 g, 0.65 mmol), and(5-methyl-1,3-dioxolane-2-one-4-yl)-methyl 4-nitrophenyl carbonate (0.22g, 0.74 mmol) were dissolved in DMF (5 ml), and the mixture was stirredat room temperature over night. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water, an aqueous saturated sodium chloride solution, andthen dried over sodium sulfate. After filtration and concentration, theresidue was purified by silica gel chromatography (n-hexane:ethylacetate) to obtain 0.44 g (43%) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[methyl-(5-methyl-2-oxo-1,-dioxol-4-yl-methoxycarbonyl)-amino]acetate as amorphous.

¹H-NMR (DMSO-d₅, 100° C.) δ ppm:

1.75-2.15 (4H, m), 2.10 (3H, s), 2.37 (6H, s), 2.96 (3H, s), 3.15-3.50(1H, m), 3.70-4.25 (3H, m), 4.91 (2H, s), 5.95-6.05 (1H, m), 6.85-7.05(2H, m), 7.10-7.45 (7H, m), 7.56 (1H, s), 9.76 (1H, br).

Example 33{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methyl)-amino]acetatehydrochloride

4-Bromomethyl-5-methyl-1,3-dioxol-2-one (0.12 g, 0.61 mmol) was added toan acetonitrile (5 ml) solution of7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ylmethylaminoacetate (0.30 g, 0.58 mmol) and triethylamine (0.10 ml, 0.69mmol), and the mixture was stirred at room temperature over night. Thereaction mixture was concentrated and water was added to the residue.The mixture was extracted with ethyl acetate, washed with an aqueoussaturated sodium chloride solution, and dried over sodium sulfate. Afterfiltration and concentration, the residue was purified by silica gelchromatography (n-hexane:ethyl acetate). The resulting residue wasdissolved in ethyl acetate, and 4N hydrochloric acid-ethyl acetate wasadded thereto to form hydrochloride and then crystallized. The resultedcrystals were collected by filtration and air-dried to obtain 90 mg(23%) of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methyl)-amino]acetatehydrochloride as white powder.

Melting point: 162.0-163.6° C.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm:

1.75-2.15 (4H, m), 2.08 (3H, s), 2.37 (6H, s), 2.45-2.55 (3H, m),3.15-4.10 (6H, m), 5.95-6.05 (1H, m), 6.85-7.05 (2H, m), 7.10-7.45 (7H,m), 7.56 (1H, s), 9.78 (1H, br).

Example 34{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[4-(2,2-dimethyl-propionyl)-piperazin-1-yl]acetatehydrochloride

1-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazinedihydrochloride (200 mg, 0.31 mmol) was dissolved in pyridine (2 ml).Trimethylacetylchloride (0.1 ml, 0.75 mmol) was added thereto, and themixture was stirred at room temperature for 20 hours. Ethyl acetate wasadded to the reaction mixture, and the mixture was washed with a coppersulfate aqueous solution and a saturated sodium sulfate aqueous solutionsequentially, dried over anhydrous sodium sulfate. After filtration andconcentration under reduced pressure, the residue was purified by silicagel flash chromatography (ethyl acetate: methanol=100:0→98:2). Thepurified product was concentrated under reduced pressure, and a 4Nhydrogen chloride ethyl acetate solution (0.5 ml) was added to the ethylacetate solution (2 ml) of the residue. To the solution was addeddiethyl ether, and the resulted precipitates were collected byfiltration and dried to obtain 70 mg of{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}[4-(2,2-dimethyl-propionyl)-piperazin-1-yl]acetatehydrochloride as white powder.

Melting point: 194-195° C.

¹H-NMR (DMSO-d₆) δ ppm:

1.20 (9H, s), 1.6-2.2 (4H, m), 2.33 (3H, s), 2.37 (3H, s), 2.7-3.0 (1H,m), 3.44 (8H, brs), 4.0-5.0 (3H, m), 6.0-6.2 (1H, m), 6.6-7.8 (10H, m),10.29 (1H, s).

Table 1 shows chemical formulae of the compounds obtained in Examples 1to 34.

TABLE 1

Example R¹ Salt  1 —CO(CH₂)₂CO₂H —  2 —CO(CH₂)₂CO₂ ⁻Na⁺ —  3—CO(CH₂)₂CO₂ ⁻K⁺ —  4 —CO(CH₂)₃CO₂ ⁻Na⁺ —  5 —CO(CH₂)₂CO₂CH₃ —  6—CO(CH₂)₂CONH(CH₂)₂OH —  7 —COCH₂SCH₂CO₂H —  8 —COCH₂SCH₂CO₂CH₃ —  9—COCH₂S(O)₂CH₂CO₂CH₃ — 10 —CO(CH₂)₁₄CH₃ — 11 —COCH₂Cl — 12

— 13

2HCl 14

2HCl 15 —CO(CH₂)₃N(CH₃)₂ HCl 16 —CO(CH₂)₃Cl — 17

— 18 —COCH₂N(CH₃)CO₂CH(CH₃)Cl 19 —COCH₂N(CH₃)CO₂CH(CH₃)OCOCH₃ — 20

— 21

— 22 —CO₂CH₂Cl — 23 —CO₂CH₂I — 24 —CO₂CH₂OCOCH₃ — 25 —CH₂SCH₃ — 26—CH₂OPO(OH)₂ — 27 —CH₂OCOCH₃ — 28 —CH₂CONH(CH₂)₂Cl — 29—CONH(CH₂)₂N⁺(CH₃)₃Cl⁻ — 30 —CO(CH₂)₂CO₂CH₂OCOC(CH₃)₃ — 31—COCH₂OCON(CH₃)CH₂CO₂CH₂CH₃ — 32

— 33

HCl 34

HCl

Example 35 to Example 104

The compounds of the following Examples 36, 37, and 63 were prepared inthe same manner as the above Example 1, using corresponding startingmaterials.

The compounds of the following Examples 62, 64, 65, 66, 86, and 87 wereprepared in the same manner as the above Example 5, using correspondingstarting materials.

The compounds of the following Examples 35, 45, 46, 47, 48, 49, 50, 51,52, 68, 92, 69, and 93 were prepared in the same manner as the aboveExample 10, using corresponding starting materials.

The compounds of the following Examples 42, 43, 67, 77, 78, 85, 95, and103 were prepared in the same manner as the above Example 12, usingcorresponding starting materials.

The compounds of the following Examples 39, 55, 56, 57, 58, 60, 61, 74,75, 76, 81, 82, and 84 were prepared in the same manner as the aboveExample 13, using corresponding starting materials.

The compounds of the following Examples 38, 41, 53, 54, 59, 70, 71, 72,73, 79, 80, and 83 were prepared in the same manner as the above Example15, using corresponding starting materials.

The compound of the following Example 91 was prepared in the same manneras the above Example 17, using corresponding starting materials.

The compounds of the following Examples 88, 89, and 90 were prepared inthe same manner as the above Example 19, using corresponding startingmaterials.

The compound of the following Example 40 was prepared in the same manneras the above Example 24, using corresponding starting material.

The compound of the following Example 44 was prepared in the same manneras the above Example 28, using corresponding starting materials.

The compound of the following Example 94 was prepared in the same manneras the above Example 32, using corresponding starting materials.

The compounds of the following Examples 96, 97, 98, 99, 100, 101, 102,and 104 were prepared in the same manner as the above Example 34, usingcorresponding starting materials.

Table 2 shows chemical formulae and the physical properties, such as NMRand MS of the compounds obtained in

Examples 35 to 104

TABLE 2

Example R¹ NMR MS Salt 35 —CO(CH₂)₄CO₂CH₃ 1H-NMR (DMSO-d6, 100° C.)δppm: 1.55-170 (4 H, m), 175-2.05 (4 H, m), 2.25-2.35 (2 H, m), 2.37 (6H, s), 2.40-2.55 (2 H, m), 3.15-3.50 (1 H, m), 3.58 (3 H, s), 3.75-4.15(1 H, m), 5.90-6.00 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.45 (7 H, m),7.56 (1 H, s), 9.79 (1 H, br). 591 — 36 —CO(CH₂)₃CO₂H 1H-NMR (DMSO-d6)δppm: 1.7-2.1 (6 H, m), 2.2-2.4 (8 H, m), 2.5-2.55 (2 H, m), 3.0-4.4 (2H, m), 5.9-6.0 (1 H, m), 6.8-7.1 (2 H, m), 7.1-7.3 (3 H, m), 7.3-7.4 (4H, m), 7.57 (1 H, s), 9.8 (1 H, br). 563 — 37 —COCH₂OCH₂CO₂H 1H-NMR(DMSO-d6) δppm: 2.2-2.6 (4 H, m), 2.37 (6 H, s), 3.0-4.4 (2 H, m), 4.13(2 H, s), 4.35 (2 H, s), 5.9-6.1 (1 H, m), 6.8-7.1 (2 H, m), 7.1-7.3 (3H, m), 7.3- 7.4 (4 H, m), 7.57 (1 H, s), 9.8 (1 H, br). 565 — 38—CO(CH₂)₂NHCO₂C(CH₃)₃ 1H-NMR (DMSO-d6) δppm: 1.38 (9 H, s), 1.6-2.2 (4H, m), 2.37 (6 H, s), 2.5-2.7 (2 H, m), 3.29 (2 H, dd, J = 6.4 Hz, 12.9Hz), 3.0-4.3 (2 H, m), 5.8-6.1 (1 H, m), 6.3 (1 H, br), 6.8-7.1 (2 H,m), 7.1-7.5 (7 H, m), 7.56 (1 H, s), 9.82 (1 H, br). 620 — 39—CO(CH₂)₂NH₂ 1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.37 (3 H, s),2.38 (3 H, s), 2.8-4.3 (2 H, m), 2.9 (2 H, t, J = 6.9 Hz), 3.1 (2 H, t,J = 6.9 Hz), 5.9-6.1 (1 H, m), 6.8- 7.1 (2 H, m), 7.1-7.3 (3 H, m),7.3-7.5 (4 H, m), 7.56 (1 H, s), 8.2 (3 H, br), 9.87 (1 H, br). 520Hydro- chloride 40 —CO₂CH₂OPO(OH)₂ 1H-NMR (DMSO-d6) δppm: 1.3-2.1 (4 H,m), 2.2-2.4 (6 H, m), 2.0-4.0 (2 H, m), 5.3-5.6 (2 H, m), 5.7-6.0 (1 H,m), 6.4-7.7 (10 H, m), 10.0 (1 H, br) 603 — 41 —CO(CH₂)₂CONH₂ 1H-NMR(Toluene-d8) δppm: 1.5-1.8 (4 H, m), 2.0-2.2 (2 H, m), 2.31 (3 H, s),2.44 (3 H, s), 2.4-2.6 (2 H, m), 2.5-5.0 (2 H, m), 4.0-4.7 (2 H, m),5.8-6.1 (1 H, m), 6.4- 6.8 (3 H, m), 6.8-7.2 (5 H, m), 7.29 (1 H, s),7.36 (1 H, s). 548 — 42 —COCH₂NHCH₂CO₂CH₃ 1H-NMR (DMSO-d6) δppm: 1.7-2.2(4 H, m), 2.38 (3 H, s), 2.39 (3 H, s), 2.8-4.3 (2 H, m), 3.75 (3 H, s),3.85 (2 H, s), 3.99 (2 H, s), 6.0-6.2 (1 H, m), 6.7-7.1 (2 H, m),7.1-7.3 (3 H, m), 7.3-7.5 (4 H, m), 7.56 (1 H, s), 9.87 (1 H, br). 578Hydro- chloride 43 —COCH₂N(CH₃)CH₂CO₂C₂H₅ 1H-NMR (DMSO-d6) δppm: 1.21 (3H, t, J = 7.1 Hz), 1.7-2.2 (4 H, m), 2.366 (3 H, s), 2.371 (3 H, s),2.59 (3 H, s), 2.8-4.3 (2 H, m), 3.61 (2 H, s), 3.77 (2 H, s), 4.14 (2H, q, J = 7.1 Hz), 5.9-6.1 (1 H, m), 6.8-7.1 (2 H, m), 7.1-7.3 (3 H, m),7.3-7.5 (4 H, m), 7.56 (1 H, s), 9.80 (1 H, br). 606 Hydro- chloride 44—CONHC₂H₅ 1H-NMR (DMSO-d6) δppm: 1.09 (3 H, t, J = 7.1 Hz), 1.6-2.2 (4H, m), 2.46 (6 H, s), 2.85 (3 H, s), 2.8-4.3 (2 H, m), 3.11 (2 H, dq, J= 7.1, 5.7 Hz), 3.6-4.6 (1 H, br), 5.7-5.9 (1 H, m), 6.6-7.2 (4 H, m),7.2-7.5 (5 H, m), 7.55 (1 H, s), 9.79 (1 H, br). 520 — 45 —CO(CH₂)₈CH₃1H-NMR(CDCl3) δppm: 0.73-0.97 (3 H, m), 1.11-2.59 (26.7 H, m), 2.68-2.89(1 H, m), 2.98-3.97 (0.3 H, m), 4.70- 5.15 (1 H, m), 5.85-6.17 (1.2 H,m), 6.46-6.67 (1 H, m), 6.84-7.68 (8.8 H, m). — — 46 —CO(CH₂)₁₀CH₃1H-NMR(CDCl3) δppm: 0.80-0.93 (3 H, m), 1.13-2.62 (30.7 H, m), 2.70-2.92(1 H, m), 2.99-3.95 (0.3 H, m), 4.70- 5.14 (1 H, m), 5.84-6.16 (1.2 H,m), 6.44-6.66 (1 H, m), 6.85-7.78 (8.8 H, m). — — 47 —CO(CH₂)₁₂CH₃1H-NMR(CDCl3) δppm: 0.79-0.95 (3 H, m), 1.10-2.63 (34.7 H, m), 2.71-2.93(1 H, m), 2.98-4.03 (0.3 H, m), 4.72- 5.13 (1 H, m), 5.88-6.16 (1.2 H,m), 6.47-6.67 (1 H, m), 6.86-7.74 (8.8 H, m). — — 48 —CO(CH₂)₁₆CH₃1H-NMR(CDCl3) δppm: 0.88 (3 H, t, J = 6.6 Hz), 1.15- 1.50 (28 H, m),1.60-1.95 (4 H, m), 2.05-2.60 (9 H, m), 2.75-2.95 (1 H, m), 4.75-5.10 (1H, m), 5.85-6.10 (1 H, m), (6.50-6.65 (1 H, m), 6.85-7.05 (3 H, m),7.15-7.75 (8 H, m). 714 — 49 —CO(CH₂)₁₈CH₃ 1H-NMR(CDCl3) δppm: 0.88 (3H, t, J = 6.7 Hz), 1.15- 1.50 (32 H, m), 1.60-2.00 (4 H, m), 2.05-2.60(9 H, m), 2.75-2.95 (1 H, m), 4.70-5.10 (1 H, m), 5.85-6.10 (1 H, m),6.45-6.65 (1 H, m), 6.85-7.10 (3 H, m), 7.15-7.75 (8 H, m). 742 — 50—COC₃H₇ 1H-NMR(CDCl3) δppm: 1.03 (3 H, t, J = 7.3 Hz), 1.6- 1.8 (4 H,m), 2.0-2.5 (4 H, m), 2.43 (3 H, s), 2.45 (3 H, s), 2.81 (1 H, t, J =11.6 Hz), 4.7-5.1 (1 H, m), 5.9-6.1 (1 H, m), 6.5-6.6 (1 H, m), 6.9-7.9(9 H, m). 519 — 51 —CO(CH₂)₄CH₃ 1H-NMR(CDCl3) δppm: 0.8-1.0 (3 H, m),1.2-1.4 (2 H, m), 1.6-1.9 (4 H, m), 2.1-2.6 (4 H, m), 2.44 (3 H, s),2.46 (3 H, s), 2.81 (1 H, t, J = 11.5 Hz), 4.7-5.1 (1 H, m), 5.8-6.1 (1H, m), 6.4-6.6 (1 H, m), 6.9-7.7 (9 H, m). 547 — 52 —CO(CH₂)₆CH₃1H-NMR(CDCl3) δppm: 0.8-1.0 (3 H, m), 1.2-1.5 (8 H, m), 1.6-1.9 (4 H,m), 2.0-2.5 (4 H, m), 2.42 (3 H, s), 2.44 (3 H, s), 2.80 (1 H, t, J =11.5 Hz), 4.7-5.1 (1 H, m), 5.9-6.1 (1 H, m), 6.5-6.6 (1 H, m), 6.9-8.0(9 H, m). 575 — 53 —COCH₂NHCOCH₂NHCO₂C(CH₃)₃ 1H-NMR(CDCl3) δppm: 1.3-1.5(9 H, m), 1.7-1.9 (2 H, m), 2.1-2.3 (2 H, m), 2.4-2.6 (6 H, m), 2.8-2.9(1 H, m), 3.6-4.3 (3 H, m), 4.7-5.0 (1 H, m), 5.1-5.3 (1 H, m), 5.7- 6.2(2 H, m), 6.5-8.0 (10 H, m). 663 — 54 —COCH₂NHCOCH₂NHCOCH₂NHCO₂C(CH₃)₃1H-NMR(CDCl3) δppm: 1.36 (9 H, s), 1.7-2.0 (2 H, m), 2.1-2.3 (2 H, m),2.4-2.6 (6 H, m), 2.7-2.9 (1 H, m), 3.8-4.4 (1 H, m), 4.7-4.8 (1 H, m),4.9-5.3 (2 H, m), 5.8- 6.2 (2 H, m), 6.5-8.2 (10 H, m). 720 — 55—COCH₂NHCOCH₂NH₂ 1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.34 (3 H, s),2.36 (3 H, s), 2.7-2.9 (1 H, m), 3.6-3.8 (2 H, m), 4.0-4.3 (2 H, m),4.6-4.8 (1 H, m), 5.9-6.1 (1 H, m), 6.6-7.8 (10 H, m), 8.19 (3 H, brs),8.8-9.0 (1 H, m), 10.27 (1 H, s). 563 Hydro- chloride 56—COCH₂NHCOCH₂NH₂ 1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.34 (3 H, s),2.36 (3 H, s), 2.6-3.0 (1 H, m), 3.2-3.3 (2 H, m), 3.9-4.2 (2 H, m),4.5-4.9 (1 H, m), 5.7-6.1 (1 H, m), 6.6-7.8 (10 H, m), 8.0-8.4 (1 H, m),10.22 (1 H, s). 563 — 57 —COCH₂NHCOCH₂NH₂ 1H-NMR (DMSO-d6) δppm: 1.6-2.2(4 H, m), 2.34 (3 H, s), 2.36 (3 H, s), 2.8-3.0 (1 H, m), 3.2-4.2 (4 H,m), 4.5-4.9 (1 H, m), 5.8-6.0 (1 H, m), 6.47 (2 H, s), 6.6- 7.8 (10 H,m), 8.5-8.7 (1 H, m), 10.24 (1 H, s). 563 Fumarate 58 —COCH₂NHCOCH₂NH₂1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.30 (3 H, s), 2.33 (3 H, s),2.36 (3 H, s), 2.8-3.0 (1 H, m), 3.4- 3.8 (2 H, m), 4.0-4.4 (2 H, m),4.6-4.9 (1 H, m), 5.8-6.0 (1 H, m), 6.6-7.8 (10 H, m), 8.03 (3 H, brs),8.7-9.0 (1 H, m), 10.25 (1 H, s). 563 Methane- sulfonate 59—COCH₂N(CH₃)CO₂C(CH₃)₃ 1H-NMR(CDCl3) δppm: 1.3-1.5 (9 H, m), 1.6-1.9 (2H, m), 2.0-2.3 (2 H, m), 2.4-2.6 (6 H, m), 2.7-3.0 (4 H, m), 3.9-4.3 (2H, m), 4.7-5.1 (1 H, m), 5.9-6.2 (1 H, m), 6.5- 6.7 (1 H, m), 6.8-7.8(10 H, m). 620 — 60 —COCH₂NHCOCH₂NHCOCH₂NH₂ 1H-NMR (DMSO-d6) δppm:1.5-2.2 (4 H, m), 2.34 (3 H, s), 2.36 (3 H, s), 2.8-3.0 (1 H, m),3.5-3.7 (1 H, m), 3.8-4.2 (6 H, m), 4.6-4.9 (1 H, m), 5.8-6.1 (1 H, m),6.4-7.8 (10 H, m), 8.11 (3 H, brs), 8.5-8.9 (2 H, m). 620 Hydro-chloride 61 —COCH₂NHCH₃ 1H-NMR (DMSO-d6) δppm: 1.7-2.2 (4 H, m), 2.33 (3H, s), 2.38 (3 H, s), 2.64 (3 H, s), 2.7-2.9 (1 H, m), 4.0-4.4 (2 H, m),4.5-4.7 (1 H, m), 6.0-6.2 (1 H, m), 6.6-7.8 (10 H, m), 9.40 (2 H, brs),10.29 (1 H, s). 520 Hydro- chloride 62 —CO(CH₂)₂CO₂C₂H₅ 1H-NMR (DMSO-d6,100° C.) δppm: 1.18 (3 H, t, J = 7.1 Hz), 1.75-2.10 (4 H, m), 2.37 (6 H,s), 2.60-2.70 (2 H, m), 2.70-2.80 (2 H, m), 3.15-3.50 (1 H, m), 3.75-4.10 (1 H, m), 4.09 (2 H, q, J = 7.1 Hz), 5.90-6.00 (1 H, m), 6.85-7.05(2 H, m), 7.10-7.25 (3 H, m), 7.30-7.45 (4 H, m), 7.55 (1 H, s), 9.76 (1H, br). 577 — 63 —CO(CH₂)₄CO₂H 1H-NMR (DMSO-d6, 100° C.) δppm: 1.50-1.70(4 H, m), 1.75-2.10 (4 H, m), 2.20-2.35 (2 H, m), 2.37 (6 H, s),2.40-2.50 (2 H, m), 3.15-3.50 (1 H, m), 3.70-4.15 (1 H, m), 5.90-6.00 (1H, m), 6.80-7.05 (2 H, m), 7.10- 7.25 (3 H, m), 7.25-7.40 (4 H, m), 7.56(1 H, s), 9.76 (1 H, br), 11.30 (1 H, br). 577 — 64 —CO(CH₂)₃CO₂CH₃1H-NMR (DMSO-d6, 100° C.) δppm: 1.70-2.15 (6 H, m), 2.35-2.45 (2 H, m),2.37 (6 H, s), 2.50-2.60 (2 H, m), 3.10-3.55 (1 H, m), 3.60 (3 H, s),3.75-4.15 (1 H, m), 5.90-6.00 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.25 (3H, m), 7.25-7.45 (4 H, m), 7.56 (1 H, s), 9.77 (1 H, br). 577 — 65—CO(CH₂)₂CO₂(CH₂)OH 1H-NMR (DMSO-d6, 100° C.) δppm: 1.75-2.10 (4 H, m),2.37 (6 H, s), 2.60-2.75 (4 H, m), 3.10-3.50 (1 H, m), 3.58 (2 H, q, J =5.4 Hz), 3.75-4.10 (1 H, m), 4.08 (2 H, t, J = 5.4 Hz), 4.24 (1 H, t, J= 5.4 Hz), 5.90-6.00 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.45 (7 H, m),7.56 (1 H, s), 9.76 (1 H, br). 593 — 66 —CO(CH₂)₂CO₂CH₂CH(CH₃)₂ 1H-NMR(DMSO-d6, 100° C.) δppm: 0.88 (6 H, d, J = 6.7 Hz), 1.75-2.05 (5 H, m),2.37 (6 H, s), 2.60-2.80 (4 H, m), 3.15-3 55 (1 H, m), 3.70-4.15 (1 H,m), 3.85 (2 H, d, J = 6.5 Hz), 5.90-6.00 (1 H, m), 6.85-7.05 (2 H, m),7.10-7.25 (3 H, m), 7.30-7.45 (4 H, m), 7.55 (1 H, s), 9.76 (1 H, br).605 — 67 —COCH₂N(CH₃)CH₂CO₂C₂H₅ 1H-NMR (CDCl3) δppm: 1.02-1.34 (3 H, m),1.43-3.72 (23 H, m), 3.75-4.28 (2 H, m), 4.69-5.19 (1 H, m), 5.85- 6.16(1.2 H, m), 6.47-6.68 (1 H, m), 7.86-8.04 (8.8 H, m). 633 — 68—COC(CH₃)₂OCOCH₃ 1H-NMR (CDCl3) δppm: 1.40-2.63 (19.6 H, m), 2.68- 2.93(1 H, m), 3.02-4.03 (0.4 H, m), 4.71-5.13 (1 H, m), 5.88-6.15 (1.2 H,m), 6.45-6.68 (1 H, m), 6.82-7.78 (8.8 H, m). 576 — 69 —COCH₃ 1H-NMR(CDCl3) δppm: 1.63-1.96 (2 H, m), 2.03-2.36 (2 H, m), 2.25 (3 H, s),2.39-2.69 (6.6 H, m), 2.72-2.95 (1 H, m), 3.09-3.89 (0.4 H, m),4.70-5.16 (1 H, m), 5.84-6.18 (1.2 H, m), 6.48-6.67 (1 H, m), 6.83-7.76(8.8 H, m). — — 70 —COCH₂NHCOCH₂N(CH₃)₂ 1H-NMR (DMSO-d6) δppm: 1.6-2.2(4 H, m), 2.34 (3 H, s), 2.37 (3 H, s), 2.5-2.9 (6 H, m), 3.9-4.1 (3 H,m), 4.1-4.5 (2 H, m), 4.5-4.9 (1 H, m), 5.8-6.1 (1 H, m), 6.6-8.0 (10 H,m), 9.1-9.4 (1 H, m), 10.11 (1 H, brs), 10.28 (1 H, s). 591 Hydro-chloride 71 —COCH₂NHCOCH₂N(CH₃)CO₂C(CH₃)₃ 1H-NMR (CDCl3) δppm: 1.47 (9H, s), 1.7-1.9 (2 H, m), 2.0-2.3 (2 H, m), 2.44 (3 H, s), 2.45 (3 H, s),2.7-3.0 (1 H, m), 2.96 (3 H, s), 3.8-4.4 (4 H, m), 4.7-5.1 (1 H, m),5.9-6.2 (1 H, m), 6.5-7.6 (10 H, m), 7.71 (1 H, brs). 677 — 72—COCH₂N(CH₃)COCH₂NHCO₂C(CH₃)₃ 1H-NMR (CDCl3) δppm: 1.44 (9 H, s),1.7-1.9 (2 H, m), 2.0-2.3 (2 H, m), 2.44 (3 H, s), 2.46 (3 H, s),2.7-3.1 (1 H, m), 3.11 (3 H, s), 3.9-4.4 (4 H, m), 4.7-5.1 (1 H, m),5.3-5.6 (1 H, m), 5.8-6.2 (1 H, m), 6.5-7.5 (10 H, m), 7.68 (1 H, brs).677 — 73 —COCH₂N(CH₃)COCH₂N(CH₃)CO₂C(CH₃)₃ 1H-NMR (CDCl3) δppm: 1.3-1.5(9 H, m), 1.5-1.9 (2 H, m), 2.0-2.3 (2 H, m), 2.44 (3 H, s), 2.46 (3 H,s), 2.7-3.1 (7 H, m), 3.7-4.4 (4 H, m), 4.7-5.1 (1 H, m), 5.8- 6.2 (1 H,m), 6.4-6.6 (1 H, m), 6.5-8.1 (10 H, m). 691 — 74 —COCH₂NHCOCH₂NHCH₃1H-NMR (DMSO-d6) δppm: 1.5-2.2 (4 H, m), 2.34 (3 H, s), 2.36 (3 H, s),2.56 (3 H, s), 2.6-2.9 (1 H, m), 3.7-3.9 (2 H, m), 3.9-4.4 (2 H, m),4.5-4.9 (1 H, m), 5.8- 6.1 (1 H, m), 6.6-7.8 (10 H, m), 9.04 (2 H, brs),9.1-9.2 (1 H, m), 10.28 (1 H, s). 577 Hydro- chloride 75—COCH₂N(CH₃)COCH₂NH₂ 1H-NMR (DMSO-d6) δppm: 1.5-2.2 (4 H, m), 2.34 (3 H,s), 2.36 (3 H, s), 2.6-3.0 (1 H, m), 3.10 (3 H, s), 3.6-4.1 (2 H, m),4.2-4.9 (3 H, m), 5.8-6.1 (1 H, m), 6.6-7.8 (10 H, m), 8.27 (3 H, brs),10.29 (1 H, s). 577 Hydro- chloride 76 —COCH₂N(CH₃)COCH₂NHCH₃ 1H-NMR(DMSO-d6) δppm: 1.5-2.2 (4 H, m), 2.34 (3 H, s), 2.36 (3 H, s), 2.53 (3H, d, J = 4.1 Hz), 2.7-3.0 (1 H, m), 3.09 (3 H, s), 3.9-4.5 (4 H, m),4.6-5.0 (1 H, m), 5.8-6.1 (1 H, m), 6.6-7.8 (10 H, m), 9.01 (2 H, brs),10.28 (1 H, s). 591 Hydro- chloride 77

1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.367 (3 H, s), 2.374 (3 H, s),2.8-4.3 (2 H, m), 2.7-3.0 (4 H, m), 3.6-3.8 (4 H, m), 4.3 (1 H, br),6.0-6.1 (1 H, m), 6.8- 7.1 (2 H, m), 7.1-7.3 (3 H, m), 7.3-7.5 (4 H, m),7.55 (1 H, s), 9.8 (1 H, br). 576 Hydro- chloride 78

1H-NMR (DMSO-d6) δppm: 1.44 (3 H, d, J = 7.1 Hz), 2.0-2.4 (4 H, m), 2.37(3 H, s), 2.38 (3 H, s), 2.8-4.3 (2 H, m), 3.73 (3 H, s), 3.9-4.0 (3 H,m), 6.0-6.1 (1 H, m), 6.8-7.1 (2 H, m), 7.1-7.3 (3 H, m), 7.3-7.5 (4 H,m), 7.54 (1 H, s) (9.86 (1 H, br). 592 Hydro- chloride 79

1H-NMR (CDCl3) δppm: 1.2-1.6 (12 H, m), 1.7-2.0 (2 H, m), 2.1-2.3 (2 H,m), 2.4-2.6 (6 H, m), 2.7-2.9 (1 H, m), 3.8-4.4 (1 H, m), 4.7-4.8 (1 H,m), 4.9-5.3 (2 H, m), 5.8-6.2 (2 H, m), 6.5-8.2 (10 H, m). 677 — 80

1H-NMR (CDCl3) δppm: 1.2-1.4 (9 H, m), 1.7-1.9 (2 H, m), 2.0-2.3 (2 H,m), 2.5-2.6 (6 H, m), 2.7-3.2 (3 H, m), 3.7-4.5 (3 H, m), 4.7-5.1 (1 H,m), 5.8-6.1 (1 H, m), 6.5-8.0 (15 H, m). 753 — 81

1H-NMR (DMSO-d6) δppm: 1.3-1.5 (3 H, m), 1.7-2.4 (4 H, m), 2.34 (3 H,s), 2.35 (3 H, s), 2.7-2.9 (1 H, m), 3.9 (1 H, brs), 4.0-4.3 (2 H, m),4.5-4.9 (1 H, m), 5.8-6.1 (1 H, m), 6.6-7.8 (10 H, m), 8.27 (3 H, brs),8.9-9.1 (1 H, m), 10.26 (1 H, s). 577 Hydro- chloride 82

1H-NMR (DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.32 (3 H, s), 2.37 (3 H, s),2.7-3.2 (3 H, m), 4.0-4.3 (3 H, m), 4.5-4.9 (1 H, m), 5.9-6.1 (1 H, m),6.6-7.7 (15 H, m), 8.27 (3 H, brs), 8.9-9.3 (1 H, m), 10.26 (1 H, s).653 Hydro- chloride 83

1H-NMR (CDCl3) δppm: 1.2-1.4 (9 H, m), 1.6-2.2 (4 H, m), 2.5-2.6 (6 H,m), 2.7-3.2 (5 H, m), 4.2-4.5 (1 H, m), 4.7-5.1 (3 H, m), 5.5-6.1 (1 H,m), 6.4-8.1 (20 H, m). 843 — 84

1H-NMR (DMSO-d6) δppm: 1.5-2.2 (4 H, m), 2.3-2.4 (6 H, m), 2.6-3.2 (5 H,m), 4.0-4.2 (1 H, m), 4.5-4.8 (2 H, m), 5.7-6.1 (1 H, m), 6.6-7.8 (20 H,m), 8.2 (3 H, brs), 9.0-9.5 (1 H, m), 10.2-10.5 (1 H, m). 743 Hydro-chloride 85

1H-NMR (DMSO-d6, 100° C.) δppm: 1.10-2.10 (17 H, m), 2.37 (6 H, s),2.60-2.80 (4 H, m), 3.15-3.50 (1 H, m), 3.75-4.20 (1 H, m), 4.45-4.65 (1H, m), 5.90-6.00 (1 H, m), 6.55-6.70 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.45 (7 H, m), 7.55 (1 H, s), 9.76 (1 H, br). 719 — 86

1H-NMR (DMSO-d6, 100° C.) δppm: 1.21 (3 H, t, J = 7.1 Hz), 1.44 (3 H, d,J = 5.4 Hz), 1.75-2.10 (4 H, m), 2.37 (6 H, s), 2.60-2.80 (4 H, m),3.15-3.50 (1 H, m), 3.60-4.10 (1 H, m), 4.13 (2 H, q, J = 7.1 Hz),5.90-6.00 (1 H, m), 6.64 (1 H, q, J = 5.4 Hz), 6.85-7.05 (2 H, m),7.10-7.45 (7 H, m), 7.55 (1 H, s), 9.75 (1 H, br). 665 — 87

1H-NMR (DMSO-d6, 100° C.) δppm: 1.75-2.05 (4 H, m), 2.11 (3 H, s), 2.37(6 H, s), 2.65-2.85 (4 H, m), 3.15-3.45 (1 H, m), 3.75-4.05 (1 H, m),4.93 (2 H, s), 5.90-6.00 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.25 (3 H,m), 7.30-7.45 (4 H, m), 7.55 (1 H, s), 9.75 (1 H, br). 661 — 88

1H-NMR (DMSO-d6, 100° C.) δppm: 1.06 (6 H, d, J = 7.0 Hz), 1.35-1.45 (3H, m), 1.60-2.10 (4 H, m), 2.37 (6 H, s), 2.45-2.60 (1 H, m), 2.95 (3 H,s), 3.10-3.50 (1 H, m), 3.75-4.15 (1 H, m), 4.17 (2 H, s), 5.95-6.05 (1H, m), 6.55-6.70 (1 H, m), 6.85-7.05 (2 H, m), 7.15- 7.45 (7 H, m), 7.56(1 H, s), 9.76 (1 H, br). 678 — 89

1H-NMR (CDCl3) δppm: 1.40-2.65 (16 H, m), 2.75- 2.90 (1 H, m), 3.80-4.25(2 H, m), 4.70-5.15 (1 H, m), 5.20-5.40 (1 H, m), 5.90-6.20 (1 H, m),6.50-8.05 (12 H, m). 636 — 90

1H-NMR (CDCl3) δppm: 0.95-2.60 (20 H, m), 2.75- 2.90 (1 H, m), 3.75-4.25(2 H, m), 4.70-5.15 (1 H, m), 5.20-5.40 (1 H, m), 5.90-6.15 (1 H, m),6.45-8.00 (12 H, m). 664 — 91

1H-NMR (CDCl3) δppm: 1.33-1.52 (9 H, m), 1.58-3.88 (26 H, m), 4.70-5.12(1 H, m), 5.88-6.18 (1.2 H, m), 6.57- 6.65 (1 H, m), 6.82-7.82 (8.8 H,m). — — 92

1H-NMR (DMSO-d6) δppm: 1.8-2.1 (4 H, m), 2.36 (3 H, s), 2.37 (3 H, s),2.8-4.3 (2 H, m), 6.2-6.3 (1 H, m), 6.8-7.1 (2 H, m), 7.1-7.5 (7 H, m),7.58 (1 H, s), 7.93 (2 H, d, J = 5.8 Hz), 8.82 (2 H, d, J = 5.8 Hz),9.82 (1 H, br). 554 Hydro- chloride 93

1H-NMR (CDCl3) δppm: 1.77-2.00 (2 H, m), 2.10-2.67 (6.6 H, m), 2.78-3.00(1 H, m), 3.07-4.04 (3.4 H, m), 4.75- 5.24 (1 H, m), 6.02-7.77 (12.6 H,m), 7.97-8.24 (2.4 H, m). — — 94

1H-NMR (DMSO-d6, 100° C.) δppm: 1.70-2.15 (4 H, m), 2.11 (3 H, s), 2.37(6 H, s), 2.95-3.50 (1 H, m), 3.60-4.25 (1 H, m), 3.95 (2 H, d, J = 6.1Hz), 4.89 (2 H, s), 5.90-6.05 (1 H, m), 6.85-7.05 (2 H, m), 7.10-7.45 (8H, m), 7.55 (1 H, s), 9.80 (1 H, br). 662 —

Example R¹⁰¹ NMR MS Salt 95 —COCH₃ 1H-NMR (DMSO-d6) δppm: 1.6-2.2 (7 H,m), 2.37 (3 H, s), 2.38 (3 H, s), 2.8-4.3 (2 H, m), 2.7-3.0 (4 H, m),3.4-3.7 (4 H, m), 3.8 (2 H, s), 5.3 (1 H, br), 6.0-6.1 (1 H, m), 6.8-7.1(2 H, m), 7.1-7.3 (3 H, m), 7.3-7.5 (4 H, m), 7.56 (1 H, s), 9.8 (1 H,br). — Hydro- chloride 96 —COC₃H₇ 1H-NMR (DMSO-d6) δppm: 0.90 (3 H, t, J= 7.4 Hz), 1.4-1.6 (2 H, m), 1.8-2.2 (4 H, m), 2.33 (3 H, s), 2.38 (3 H,s), 2.7-3.0 (1 H, m), 3.40 (8 H, brs), 3.8-5.0 (5 H, m), 5.9-6.2 (1 H,m), 6.6-7.8 (10 H, m), 10.28 (1 H, s). 645 Hydro- chloride 97 —COC₆H₅1H-NMR (DMSO-d6) δppm: 1.5-2.3 (4 H, m), 2.33 (3 H, s), 2.37 (3 H, s),2.6-2.8 (1 H, m), 3.62 (8 H, brs), 3.8-4.9 (3 H, m), 5.9-6.2 (1 H, m),6.6-7.8 (15 H, m), 10.28 (1 H, s). 679 Hydro- chloride 98 —CO(CH₂)₁₄CH₃1H-NMR (DMSO-d6) δppm: 0.85 (3 H, t, J = 6.4 Hz), 1.23 (24 H, brs), 1.48(2 H, brs), 1.7-2.2 (4 H, m), 2.34 (3 H, s), 2.38 (3 H, s), 2.7-2.9 (1H, m), 3.40 (8 H, brs), 3.6-5.0 (5 H, m), 5.9-6.2 (1 H, m), 6.6-7.8 (10H, m), 10.30 (1 H, s). 813 Hydro- chloride 99 —CO(CH₂)₂CO₂H 1H-NMR(DMSO-d6) δppm: 1.6-1.9 (4 H, m), 2.1-2.3 (2 H, m), 2.4-2.9 (10 H, m),3.2-3.8 (9 H, m), 4.7-5.1 (1 H, m), 5.9-6.2 (2 H, m), 6.5-6.7 (1 H, m),6.8-8.0 (10 H, m). 675 Hydro- chloride 100  —CO(CH₂)₂CO₂C₂H₅ 1H-NMR(DMSO-d6) δppm: 1.17 (3 H, t, J = 7.1 Hz), 1.6-2.2 (4 H, m), 2.33 (3 H,s), 2.38 (3 H, s), 2.5-2.9 (4 H, m), 3.39 (8 H, brs), 4.0-5.0 (4 H, m),4.03 (2 H, q, J = 7.1 Hz), 5.9-6.2 (1 H, m), 6.6-7.8 (10 H, m), 10.28 (1H, s), 10.8 (1 H, brs). 703 Hydro- chloride 101  —CO(CH₂)₃CO₂C₂H₅ 1H-NMR(DMSO-d6) δppm: 1.18 (3 H, t, J = 7.1 Hz), 1.6-2.3 (6 H, m), 2.33 (3 H,s), 2.38 (3 H, s), 2.7-3.0 (4 H, m), 3.42 (8 H, brs), 4.0-4.9 (4 H, m),4.05 (2 H, q, J = 7.1 Hz), 5.9-6.2 (1 H, m), 6.6-7.8 (10 H, m), 10.20 (1H, s), 11.0 (1 H, brs). 717 Hydro- chloride 102  —CO(CH₂)₂CO₂CH₃ 1H-NMR(DMSO-d6) δppm: 1.6-2.2 (4 H, m), 2.33 (3 H, s), 2.38 (3 H, s), 2.5-3.0(4 H, m), 3.36 (8 H, brs), 3.56 (3 H, s), 4.0-5.0 (4 H, m), 5.9-6.2 (1H, m), 6.6-7.8 (10 H, m), 10.27 (1 H, s). 689 Hydro- chloride 103 

1H-NMR(CDCl3) δppm: 1.67-1.93 (2 H, m), 2 03-2.32 (2 H, m), 2.38-2.94(11 H, m), 3.16-4.12 (7 H, m), 4.75- 5.14 (1 H, m), 5.92-7.68 (14 H, m).669 — 104  —(CH₂)₂O(CH₂)₂OH 1H-NMR(CDCl3) δppm: 1.02-1.34 (3 H, m),1.43-3.72 (23 H, m), 3.75-4.28 (2 H, m), 4.69-5.19 (1 H, m), 5.85-6.16(1.2 H, m), 6.47-6.68 (1 H, m), 7.86-8.04 (8.8 H, m). 633 —

Test Example 1

The compounds obtained in Examples 1, 50, and 52 were used as testcompounds.

Each test compound, (Examples 1, 50, and 52) equivalent to 10 mg oftolvaptan, and hypromellose (125 mg) were suspended in 25 ml of waterfor injection in a porcelain mortar, to thereby obtain a suspensionequivalent to 0.4 mg of tolvaptan per ml of suspension.

A spray-dried tolvaptan powder equivalent to 60 mg of tolvaptan, whichwas prepared in a similar manner to Example 3 of Japanese UnexaminedPatent Publication No. 1999-21241, was suspended in 50 ml of water forinjection in a porcelain mortar. This suspension was diluted three-foldwith water for injection, preparing a suspension of spray-dried powderequivalent to 0.4 mg of tolvaptan per ml of suspension.

The following tests were conducted to examine the oral absorptionfeatures of each suspension. Male rats (body weight: about 180 g) thathad been deprived of food for about 18 hours were used as test animals.The above suspensions were each administered by forced oraladministration using a sonde for oral administration at a dose of 2.5ml/kg of body weight, producing 1 mg of tolvaptan per kg of body weight.The blood samples were collected from the jugular vein under lightdiethyl ether anesthesia at the time of 0.5 hour, 1 hour, 2 hours, 4hours, 6 hours, and 8 hours later after dosing. The serum concentrationsof tolvaptan (ng/ml) were determined by using HPLC-MS/MS (Waters).

The average pharmacokinetic parameters were calculated from the results.The results are shown in the following table.

TABLE 3 Test AUC_(∞) C_(max) T_(max) MRT_(∞) Compound (ng · hr/mL)(ng/mL) (hr) (hr) Tolvaptan 80.9 ± 28.5 26.4 ± 12.9 1.50 ± 0.58 2.95 ±0.35 Example 1 96.1 ± 18.1 16.2 ± 4.8  2.00 ± 0.00 4.45 ± 0.64 Example50 117.0 ± 26.1  21.6 ± 3.0  2.00 ± 0.00 4.78 ± 0.40 Example 52 78.8 ±41.7 11.6 ± 11.1 2.67 ± 1.15 9.10 ± 7.98 Mean ± S.D. (n = 3 or 4)

Table 3 reveals that, when administered in vivo, the test compoundsindicate smaller Cmax than tolvaptan and the maximum drug concentrationtimes (T_(max)) of the test compounds are delayed compared to tolvaptan.Consequently, the test compounds have prolonged effects.

Test Example 2

The compounds obtained in Examples 74 was used as test compounds.

The test compound, (Examples 1) equivalent to 10 mg of tolvaptan, andhydroxypropylcellulose (5 mg) was dissolved in 25 ml of water forinjection in a porcelain mortar, to thereby obtain a solution equivalentto 0.4 mg of tolvaptan per ml.

A spray-dried tolvaptan powder equivalent to 10 mg of tolvaptan wassuspended in 25 ml of water for injection in a porcelain mortar, toobtain a suspension of spray-dried powder equivalent to 0.4 mg oftolvaptan per ml of suspension.

The following tests were conducted to examine the oral absorptionfeatures of each suspension and solution. Male rats (body weight: about160 g) that had been fasted for about 18 hours were used as testanimals. The above suspension or solution were each administered byforced oral administration using a sonde for oral administration at adose of 2.5 ml/kg of body weight, producing 1 mg of tolvaptan per kg ofbody weight. The blood samples were collected from the jugular veinunder light diethyl ether anesthesia at the time of 0.5 hour, 1 hour, 2hours, 3 hours, 4 hours, 6 hours, 8 hours and 10 hours later afterdosing. The serum concentrations of tolvaptan (ng/ml) were determined byusing HPLC-MS/MS (Waters).

The average pharmacokinetic parameters were calculated from the results.The results are shown in the following table.

TABLE 4 Test AUC_(∞) C_(max) T_(max) MRT_(∞) Compound (ng · hr/mL)(ng/mL) (hr) (hr) Tolvaptan 92.4 ± 27.0  26.9 ± 11.6 1.00 ± 0.00 2.96 ±0.47 Example 74 79.0 ± 15.6 14.8 ± 6.4 4.00 ± 1.41 5.22 ± 0.51 Mean ±S.D. (n = 4)

Table 4 reveals that, when administered in vivo, the maximum drugconcentration time (T_(max)) of the test compound is delayed compared totolvaptan, and that the mean residence time (MRT) of the test compoundis longer than that of tolvaptan. Consequently, the test compound hasprolonged effect.

1. A benzazepine compound represented by general formula (1)

wherein R¹ is a group of (1-1) to (1-7): (1-1) a —CO—(CH₂)_(n)—COR²group wherein n is an integer of 1 to 4, R² is (2-1) a hydroxy group;(2-2) a lower alkoxy group optionally substituted with a hydroxy group,a lower alkanoyl group, a lower alkanoyloxy group, a loweralkoxycarbonyloxy group, a cycloalkyloxycarbonyloxy group, or5-methyl-2-oxo-1,3-dioxol-4-yl; or (2-3) an amino group optionallysubstituted with a hydroxy-lower alkyl group; (1-2) a—CO—(CH₂)_(m)—NR³R⁴ group wherein m is an integer of 0 to 4, R³ is ahydrogen atom or a lower alkyl group, R⁴ is (4-1) a hydrogen atom; (4-2)a lower alkyl group optionally substituted with a halogen atom, a loweralkylamino group, a lower alkoxycarbonyl group, or5-methyl-2-oxo-1,3-dioxol-4-yl; or (4-3) a lower alkoxycarbonyl groupoptionally substituted with a halogen atom, a lower alkanoyloxy group,or 5-methyl-2-oxo-1,3-dioxol-4-yl, R³ and R⁴ may form a 5- to 6-memberedsaturated heterocyclic ring by bonding R³ and R⁴ to each other, togetherwith the nitrogen atom to which R³ and R⁴ bond, directly or via anitrogen atom or oxygen atom, the heterocyclic ring being optionallysubstituted with (4-4) a lower alkyl group optionally substituted with ahydroxy-lower alkoxy group; (4-5) a lower alkoxycarbonyl group; (4-6) analkylcarbonyl group (optionally substituted on the alkyl group with acarboxyl group or a lower alkoxycarbonyl group); (4-7) an arylcarbonylgroup; or (4-8) a furylcarbonyl group; (1-3) a —CO—(CH₂)_(p)—O—CO—NR⁵R⁶group wherein p is an integer of 1 to 4, R⁵ is a lower alkyl group, andR⁶ is a lower alkoxycarbonyl-lower alkyl group; (1-4) a—CO—(CH₂)_(q)—X—R⁷ group wherein q is an integer of 1 to 4, X is anoxygen atom, a sulfur atom, or a sulfonyl group, and R⁷ is acarboxy-lower alkyl group, or a lower alkoxycarbonyl lower alkyl group;(1-5) a —CO—R⁸ group (wherein R⁸ is (8-1) an alkyl group optionallysubstituted with a halogen atom, a lower alkanoyloxy group, or a phenylgroup (substituted with a dihydroxy phosphoryloxy group in which thehydroxy groups are optionally substituted with benzyl groups, and alower alkyl group, (8-2) a lower alkoxy group substituted with a halogenatom, a lower alkanoyloxy group, or a dihydroxyphosphoryloxy group,(8-3) a pyridyl group, or (8-4) a lower alkoxyphenyl group; (1-6) alower alkyl group substituted with a group selected from the groupconsisting of lower alkylthio groups, a dihydroxyphosphoryloxy group,and lower alkanoyloxy groups; and (1-7) an amino acid or peptide residueoptionally protected with one or more protecting groups; or a saltthereof.
 2. The compound according to claim 1, wherein, in formula (1),R¹ is a group selected from the group consisting of: —CO—(CH₂)_(n)—COOH,wherein n is an integer of 1 to 4; —CO—R⁸, wherein R⁸ is an alkyl group;and, an amino acid or peptide residue optionally protected with one ormore protecting groups; or a salt thereof.
 3. The compound according toclaim 1, wherein, in formula (1), R¹ is alanyl, sarcosyl, N-ethylglycyl,N-propylglycyl, N-methyl-N-ethylglycyl, N-methyl-N-propylglycyl,N-methyl-N-butylglycyl, N-methyl-N-pentylglycyl, orN-methyl-N-hexylglycyl; or a peptide residue selected from the groupconsisting of: sarcosyl-glycyl, glycyl-glycyl, glycyl-sarcosyl,glycyl-alanyl, alanyl-glycyl, sarcosyl-sarcocyl, glycyl-phenylalanyl,phenylalanyl-glycyl, phenylalanyl-phenylalanyl, glycyl-glycyl-glycyl,N,N-dimethylglycyl-glycyl, N-methyl-N-ethylglycyl-glycyl,sarcosyl-glycyl-glycyl, and N,N-dimethylglycyl-glycyl-glycyl, each ofwhich is optionally protected with one or more protecting groups; or asalt thereof.
 4. The compound according to claim 3, wherein, in formula(1), R¹ is a peptide residues selected from the group consisting of:sarcosyl-glycyl, glycyl-glycyl, glycyl-sarcosyl, glycyl-alanyl,alanyl-glycyl, glycyl-phenylalanyl, phenylalanyl-glycyl,phenylalanyl-phenylalanyl, glycyl-glycyl-glycyl,N,N-dimethylglycyl-glycyl, N-methyl-N-ethylglycyl-glycyl, andN,N-dimethylglycyl-glycyl-glycyl, each of which is optionally protectedwith one or more protecting groups; or a salt thereof.
 5. Apharmaceutical preparation comprising the benzazepine compound of claim1 or a pharmacologically acceptable salt thereof, and apharmacologically acceptable diluent and/or carrier.
 6. Thepharmaceutical preparation according to claim 5 which is used as avasodilator, hypotensive drug, aquaretic agent, or platelet aggregationinhibitor.